Functional Microanatomy of Neurons

Medical Neuroscience | Tutorial Notes

Functional Microanatomy of Neurons

MAP TO NEUROSCIENCE CORE CONCEPTS1

NCC1. The brain is the body's most complex organ.
NCC2. Neurons communicate using both electrical and chemical signals.

LEARNING OBJECTIVES
After study of the assigned learning materials, the student will:
1. Differentiate the basic classes of cells found in the central nervous system (CNS).
2. Characterize the “functional microanatomy” of neurons (differentiate neuronal cell bodies,
dendrites, axons and synapses).
3. Describe the microanatomical composition of gray matter and white matter in the CNS.

TUTORIAL OUTLINE

I. Functional microanatomy of neurons

A. general features of neurons
1. Neurons are the fundamental unit of function in the CNS
2. possess all cellular and metabolic machinery common to all other somatic cells
(see Figure 1.32)
3. but they are distinguished from most other somatic cells by their:
a. rich diversity in morphology (shape)
b. bioelectrical properties (they generate electrical signals)
c. specializations for intercellular communication
B. survey of neuronal microanatomy (see Figure 1.2)
1. cell body, also called a soma (= “body”; plural = somata)
a. contains nucleus, nucleic acids, and the usual organelles
b. typically, neurons are very active metabolically in order to support
neural signaling and the synthetic requirements that are necessary to
maintain the intricate protoplasmic processes that arise from neuronal
somata
1
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about the brain and nervous system, the most complex living structure known in the universe.
2 Figure references to Purves et al., Neuroscience, 5th Ed., Sinauer Assoc., Inc., 2012. [click here]

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 Functional Microanatomy of Neurons

2. dendrites
a. short (usually, about 100 microns in length) protoplasmic extensions
that arise from somata
b. primarily involved in receiving neural signals from other neurons
c. dendritic spines
i. neurons that excite their synaptic partners have very
short “spines” (that typically resemble tiny mushrooms)
or short filaments along the length of their dendrites
ii. spines are primarily the sites where dendrites receive
excitatory signals from the axon terminals of other
neurons
iii. the dendrites of some neurons lack spines and are
called “smooth”; these neurons typically inhibit their
synaptic partners
d. exhibit an especially rich diversity of morphology among
different classes of neurons
i. pyramidal neurons in the cerebral cortex have a single
long “apical” dendrite and numerous shorter “basal”
dendrites
ii. other neurons are “multipolar”, meaning that their
dendrites emanate from the soma in a somewhat
regular array
3. axons
a. long protoplasmic extension that arises from somata
b. for some neurons, the axons are very short (<100 μm); for others, axons
can be very long (> 1 meter!)
c. involved in the transmission or sending of neural signals away from the
cell body and toward other neurons or effector cells
4. synaptic terminals or “synapses”
a. specialized contacts among neurons and between neurons and effector
cells
b. synapses may be “electrical” (the small minority in the mature CNS) or
“chemical” (the vast majority in the mature CNS) (see Figures 5.1 & 5.3)
c. usually found at the end of axons, with an axon terminal contacting a
dendrite of another neuron
d. however, axon terminals may contact cell bodies or even other axon
terminals

II. Neural tissue

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 Functional Microanatomy of Neurons

A. gray matter
1. appears somewhat darker in coloration (brown or gray) when observed in a
brain that is cut open obtained at autopsy
2. contains:
a. neurons (cell bodies, dendrites, axons, and axon terminals or synapses)
b. glial cells
c. vascular endothelium
B. white matter
1. appears somewhat lighter in coloration (light tan or white) when observed in a
brain that is cut open obtained at autopsy
2. contains:
a. the axons of neurons (but—with rare exceptions—no cell bodies,
dendrites, or axon terminals)
b. glial cells (those that make myelin—insulation around axons)
c. vascular endothelium

III. classes of neurons (see Figure 1.2)

a. projection neurons
i. characterized by long axons that project far from somata
(“project” signals to a distant target) (see blue cells in Figure
26.2)
ii. some project away from the CNS in peripheral nerves (see
Figure 1.7)
- afferent neurons: projection neurons that receive
information from the environment (e.g., via sensory
receptors)
- efferent neurons: projection neurons that send
information out to effector cells (e.g., via nerves to
muscle cells or glands)
iii. however, projection neurons also make shorter connections to
nearby neurons via axon collaterals
iv. most projection neurons are excitatory (i.e., they “excite” their
targets)
b. interneurons
i. characterized by shorter axons that project only a short distance
(100s of microns) in the CNS to nearby neurons

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 Functional Microanatomy of Neurons

ii. many are excitatory (see green cells in Figure 26.2), but most
are inhibitory (they prevent their targets from becoming
“excited”) (see purple cell in Figure 1.7)

STUDY QUESTIONS
How does information flow through a neuron?
A. dendrite --> synapse --> cell body --> axon--> dendrite
B. synapse --> dendrite --> axon--> cell body --> synapse
C. synapse --> dendrite --> cell body --> axon--> synapse
D. axon--> dendrite --> synapse --> cell body --> axon

Which set of microanatomical structures are typically found in white matter?

A. synapses, vascular endothelium, neuronal cell bodies, axons
B. vascular endothelium, axons
C. synapses, vascular endothelium, neuronal cell bodies
D. vascular endothelium, neuronal cell bodies, axons

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 Non-Neural Cells of the CNS

Medical Neuroscience | Tutorial Notes

Non-Neuronal Cells of the CNS

MAP TO NEUROSCIENCE CORE CONCEPTS1

NCC2. The brain is the body's most complex organ.

LEARNING OBJECTIVES
After study of the assigned learning materials, the student will:
1. Describe the basic classes of cells found in the central nervous system (CNS).
2. Describe the basic functions of the three types of glial cells found in the CNS.
3. Characterize the blood-brain barrier.

TUTORIAL OUTLINE

I. Neuroglia (or just “Glia” for short)

A. general functions of neuroglia in the CNS
1. support the metabolic and signaling functions of neurons
2. participates in neuron circuit formation and synaptic plasticity
3. make myelin (axonal insulation)
4. contribute to formation of blood-brain barrier
5. participate in inflammatory response in injured neural tissue, including
phagocytosis of cellular debris
6. contribute to the formation of scar tissue in damaged neural tissue
B. major types of neuroglia (see Figure 1.52)
1. astrocytes
a. found primarily in gray matter, because they are closely associated with
neuronal cell bodies, dendrites and synapses
b. help maintain ionic balance of extracellular fluids
c. remove and process neurotransmitters from synaptic clefts
d. assist in the formation of new synapses (“synaptogenesis”)

1
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about the brain and nervous system, the most complex living structure known in the universe.
2 Figure references to Purves et al., Neuroscience, 5th Ed., Sinauer Assoc., Inc., 2012. [click here]

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 Non-Neural Cells of the CNS

e. contribute to formation of blood-brain barrier and brain-ependymal

(ventricular) barrier (see below)
f. contribute to the formation of scars that fill-in small spaces that have
been cleared of necrotic neural tissue following injury
2. oligodendrocytes
a. form myelin in the CNS and are found, therefore, primarily in white
matter (a different cell type, the Schwann cell, makes myelin in
peripheral nerves)
b. myelin aids in the propagation of neural signals along myelinated axons
(see Figure 3.11)
i. insulate by generating layers of membrane that wrap around a
segment of an axon; this decreases the ionic (electrical)
“leakiness” of the axonal membrane
ii. gaps between myelin segments, called “nodes of Ranvier”,
allow for the economical concentration of ion channels and ion
pumps that are necessary for electrical signaling in axons (fewer
channels are needed to propagate electrical signals than would
be needed without myelin)
c. oligodendrocytes present antigens that influence the outgrowth of
axons in developing and recovering brain
d. unfortunately, subject to immunological attack in certain diseases of the
CNS (e.g., multiple sclerosis)
3. microglia
a. special type of mononuclear phagocyte that resides in the CNS
b. derived primarily from hematopoietic precursor cells that migrate into
the brain during development
c. exists in one of two forms: amoeboid and ramified
i. the ramified form is the dormant state
ii. the amoeboid form is the activated, mobile state when
microglia cells are engaged in phagocytic activity
iii. activated microglia secrete signaling molecules (cytokines) that
modulate local inflammatory responses in injured tissue
4. glial stem cells
a. subset of astrocytes located near the ventricles, often adjacent to blood
vessels
i. may give rise to more stem cells, mature astrocytes or
oligodendrocytes, or mature neurons

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 Non-Neural Cells of the CNS

ii. exhibit key properties of somatic stem cells: proliferation, self-

renewal, and the potency to make all the cells of a given tissue
(CNS, in this case)
b. oligodendroglial precursors scattered throughout the white matter
i. mainly give rise to mature olgiodendrocytes, but may also
generate astrocytes and neurons under certain conditions
c. although the discovery of these intrinsic stem cells in the CNS has
garnered an intense amount of current research activity, the functional
and clinical significance of these populations of stem cells remains
unclear
C. more on the blood-brain barrier (see Figure A20)
1. specialized permeability barrier between the capillary endothelium and the
extracellular space in neural tissue
a. formed by tight junctions between capillary endothelial cells, which are
surrounded by “end-feet” processes of astrocytes (forming a “glia
limitans”, or limiting glial border)
b. exclude large, water soluble molecules from freely diffusing into CNS, as
well as pathogenic microbes and certain toxins
c. some molecules, such as glucose and certain amino acids, are
transported passive or actively across the capillary endothelium
d unfortunately, this barrier also prevents the administration of many
potentially useful pharmaceutical agents (e.g., dopamine)
e. across the lifespan, the blood-brain barrier remains porous in certain
regions of the CNS that are involved in hormone secretion (e.g., median
eminence of the hypothalamus; pineal gland)

STUDY QUESTION
Consider a patient with a stroke that caused a small region of brain damage. Which happened first?
A. Microglia were stimulated to convert from ramified to amoeboid states.
B. Astrocytes formed scar tissue to fill-in space vacated by damaged tissue.
C. Microglia phagocytosed cellular debris.
D. Glial stem cells repopulated region of damage neural tissue.

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 Basic Orientation in the Human CNS

Medical Neuroscience | Tutorial Notes

Basic Orientation in the Human CNS

MAP TO NEUROSCIENCE CORE CONCEPTS1

NCC1. The brain is the body's most complex organ.

LEARNING OBJECTIVES
After study of the assigned learning materials, the student will:
1. Discuss position in various divisions of the central nervous system (CNS) using the following pairs
of direction terms: anterior/posterior; rostral/caudal; superior/inferior; dorsal/ventral; and
medial/lateral
2. Demonstrate the three orthogonal planes that are used to section the CNS.

NARRATIVE
by Leonard E. WHITE and Nell B. CANT
Duke Institute for Brain Sciences
Department of Neurobiology
Duke University School of Medicine

Specification of location in the nervous system

The terms used to specify location in the central nervous system are the same as those used in gross
vertebrate anatomy. One complication (that can become a source of confusion if you don’t understand
it) arises because some terms refer to the long axis of the body, which is straight, and others refer to the
long axis of the central nervous system, which has a bend in it (see Figure A1A2). A flexure in the long
axis of the nervous system arose as humans evolved upright posture. This flexure leads to a ~120 degree
angle between the long axes of the hindbrain and forebrain. The two axes intersect at the junction of
the midbrain and diencephalon.

This flexure has consequences for the application of standard anatomical terms used to specify location.
The terms anterior and posterior and superior and inferior are used with reference to the long axis of
the body, which is straight. Therefore, these terms refer to the same direction in space for both the
forebrain and the hindbrain. In contrast, the terms dorsal and ventral and rostral and caudal are used
with reference to the long axis of the nervous system, which bends. Thus, dorsal is toward the back for
the hindbrain, but toward the top of the head for the forebrain. Ventral is toward the gut. Rostral is
toward the top of the head for the hindbrain, but toward the front for the forebrain. Caudal is opposite.

1
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about the brain and nervous system, the most complex living structure known in the universe.
2 Figure references to Purves et al., Neuroscience, 5th Ed., Sinauer Assoc., Inc., 2012. [click here]

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 Basic Orientation in the Human CNS

When you understand these terms and how they are used, you will see why the terminology of
neuroanatomy can be confusing at first. For example, the ventral aspect of the spinal cord is also
referred to as the anterior aspect in humans, since for the human spinal cord, the two words are
synonymous. However, there is a nucleus (cluster of neurons) in the thalamus called the “ventral
anterior nucleus”. When reference is to the forebrain, the two terms specify different directions, so the
compound name of this nucleus is not redundant.
Use of the terms discussed in this section allows us to specify the location of any part of the nervous
system with reference to any other part.

The standard planes of section

The brain is commonly cut in one of the three standard planes of section that you may be familiar with
from your studies of human (or mammalian) anatomy (see Figure A1B). Magnetic resonance images
(MRIs) are also usually made in these planes (or close approximations of them). It will help you to
understand three-dimensional relationships in the brain if you become familiar with these planes, the
application of the positional terms discussed above, and the appearance of the internal structures of the
brain in all three planes of section.
The horizontal or axial plane (hint: think, horizon) shows structures as they would appear from above or
below. The frontal or coronal plane (hint: think, tiara-style crown) shows structures as they would
appear from the front or back. The sagittal plane shows structures as they would appear from the side
(hint: think, Sagittarius—the archer’s plane).

Other pairs of terms that are important to know are:

Lateral—toward the side and away from the midline

Medial—toward the midline and away from the side

Ipsilateral—on the same side (as another structure)

Contralateral—on the opposite side

Because of the flexure at the junction of the midbrain and diencephalon, coronal sections are the closest
to cross-sections of the forebrain, whereas horizontal sections are the closest to cross-sections of the
brainstem. (Cross-sections—also called transverse sections—are sections cut perpendicular to the long
axis of the CNS.) Your first task when confronted with a new section of the brain is to figure out the
plane of section.

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 Basic Orientation in the Human CNS

STUDY QUESTIONS
In conventional human radiological imaging (e.g., MRI, PET, CT) of the head, the axial plane is
synonymous with the horizontal plane. Which of the following statements about this plane is most
accurate?
A. The axial plane is parallel to the coronal plane.
B. The axial plane is parallel to the sagittal plane.
C. The axial plane is parallel to the floor of the cranium.
D. The axial plane is in the plane of the face.
E. The long axis of the spinal cord is in the axial plane of the cranium.

Of the following pairs of directional terms, which pair contains terms that define PERPENDICULAR
(orthogonal) directions when applied to the identified region of the central nervous system? [hint: you
may wish to extend your arms and point in the indicated directions]
A. in the forebrain, rostral & anterior
B. in the forebrain, dorsal & superior
C. in the forebrain, ventral & inferior
D. in the brainstem, ventral & anterior
E. in the spinal cord, caudal & posterior

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 Lateral Surface of the Brain

Medical Neuroscience | Tutorial Notes

Lateral Surface of the Brain

MAP TO NEUROSCIENCE CORE CONCEPTS1

NCC1. The brain is the body's most complex organ.

LEARNING OBJECTIVES
After study of the assigned learning materials, the student will:
1. Demonstrate the four paired lobes of the cerebral cortex and describe the boundaries of each.
2. Sketch the major features of each cerebral lobe, as seen from the lateral view, identifying major
gyri and sulci that characterize each lobe.

NARRATIVE
by Leonard E. WHITE and Nell B. CANT
Duke Institute for Brain Sciences
Department of Neurobiology
Duke University School of Medicine

Overview
When you view the lateral aspect of a human brain specimen (see Figures A3A and A102), three
structures are usually visible: the cerebral hemispheres, the cerebellum, and part of the brainstem
(although the brainstem is not visible in the specimen photographed in lateral view for Fig. 1 below). The
spinal cord has usually been severed (but we’ll consider the spinal cord later), and the rest of the
subdivisions are hidden from lateral view by the hemispheres. The diencephalon and the rest of the
brainstem are visible on the medial surface of a brain that has been cut in the midsagittal plane. Parts of
all of the subdivisions are also visible from the ventral surface of the whole brain. Over the next several
tutorials, you will find video demonstrations (from the brain anatomy lab) and photographs (in the
tutorial notes) of these brain surfaces, and sufficient detail in the narrative to appreciate the overall
organization of the parts of the brain that are visible from each perspective. As you work through this
text and if you have access to an interactive digital atlas of the human brain, such as Sylvius4 Online,
find the structures and regions that are described here3.
The cerebral hemispheres are especially large in humans. They are entirely covered by a 2–3-mm thick
layer of cells and cellular processes called the cerebral cortex. The surface of each hemisphere is highly

1
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about the brain and nervous system, the most complex living structure known in the universe.
2 th
Figure references to Purves et al., Neuroscience, 5 Ed., Sinauer Assoc., Inc., 2012. [click here]
3
To do so, launch Sylvius4 Online and go to Photographic Atlas, then select one of the atlas filters, such as Gyri, Lobes, or
Sulci and Fissures.

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 Lateral Surface of the Brain

infolded; the ridges thus formed are known as gyri (singular: gyrus) and the valleys are called sulci
(singular: sulcus) or fissures (if they are especially deep). The appearance of the sulci and gyri varies
somewhat from brain to brain. (As you might guess, each one has its own name, but it is necessary to
become familiar with only a few of them.) The hemispheres are conventionally divided into lobes named
for the bones of the skull that overlie them, namely the frontal, parietal, occipital and temporal lobes
(see Figure A3).

If it were possible to unfold the cerebral cortex from one hemisphere (which can be
done in digital representations of the cerebral hemisphere), the surface area of the
resulting, flattened cerebral cortex would be roughly approximated by the crust of a
13-inch pizza (thin crust, New York style, of course, given the thinness of the cortex).

Lateral aspect of the brain

The frontal lobe is the most anterior of the four lobes and is separated from the parietal lobe by the
central sulcus, which is one of the most important landmarks in the cerebral cortex (in Figure A3,
boundary between blue and red colored regions; see tutorial on Finding the Central Sulcus). An
important gyrus in the frontal lobe is the precentral gyrus. (The prefix ‘pre,’ when used to refer to
anatomical position, refers to something that is in front of something else or that is anterior.) The cortex
of the precentral gyrus is the somatic ‘motor cortex,’ which contains neurons whose axons project to the
motor nuclei in the brainstem and spinal cord that innervate the striated muscles of the body.
Fine, skilled movements are dependent on the integrity of the motor cortex (and, of course, the axons
extending from it). The axons that arise from neurons in the motor cortex and extend to the spinal cord
are known as the corticospinal tract. Those axons that extend from the motor cortex to nuclei in the
brainstem are known as the corticobulbar tract. (The brainstem is sometimes referred to as ‘bulbar’
because it has a shape resembling a bulb.) While you can’t see the individual fibers that make up the
tracts, you can see the structures through which they pass as they course between the cortex and their
targets in the brainstem and spinal cord.
On the inferior-lateral aspect of the hemisphere, you should readily appreciate a deep, fairly straight
fissure that separates the frontal and parietal lobes from the temporal lobe; this space is called the
lateral fissure or Sylvian fissure, named after the important Renaissance neuroanatomist, Franciscus
Sylvius4. If viewed from above, you would see that the hemispheres are separated by an even deeper
fissure called the longitudinal fissure (or superior sagittal fissure) (see Figure A11). The gyral formations
anterior to the precentral gyrus on the dorsal-lateral aspect of the frontal lobe between the lateral
fissure and the longitudinal fissure can be recognized as three parallel, longitudinal gyri. Adjacent to the
longitudinal fissure is the superior frontal gyrus, which is typically the most obvious of the three. This
gyrus continues on the medial surface of the hemisphere in the depths of the longitudinal fissure; we
will see it again when we examine the midsagittal section through the brain. Just inferior to the superior
frontal gyrus is the middle frontal gyrus, with the superior frontal sulcus separating the two. Note that
these two gyral formations are fairly straight and parallel to the longitudinal fissure in the parasagittal
plane. At their posterior end, they sometimes merge with the precentral gyrus, which forms, of course,
the anterior bank of the central sulcus. However, there is often an interrupted (i.e., a superficially
discontinuous) sulcus that separates them from the precentral gyrus, named the precentral sulcus.

4
Franciscus Sylvius was the inspiration for the title of our digital brain atlas, Sylvius4 Online; click here for more on
this important figure in the history of human neuroanatomy.

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 Lateral Surface of the Brain

Fig. 1. Lateral surface of the human brain. This figure is not labeled so that you may refer to it for review; see
Figures A3 & A10 for an illustrated and labeled view of the same hemisphere. (Image from Sylvius4 Online)

Just inferior to the middle frontal gyrus, across the inferior frontal sulcus, is a much more complex gyral
formation. For our purposes, we won’t be concerned with the names of these subcomponents or their
differential functional contributions to cognition and behavior. Suffice it to say that the inferior frontal
gyrus contains a critical functional division of the motor cortex that participates in the production of
speech. This division has a special name, Broca’s Area, given in honor of the famous French neurologist,
Pierre Paul Broca5, who first recognized the significance of this gyral formation for human speech in the
mid-19th century. Interestingly, the left hemisphere is dominant in most individuals (especially males
and right-handers) for this function, such that damage to the left inferior frontal gyrus is more likely to
produce an impairment of language expression, called Broca’s aphasia (aphasia means “without
speech”), than a comparable lesion involving the right inferior frontal gyrus. Interestingly, this is also the
division of the premotor cortex where in non-human primates neurons with “mirror” properties have
been characterized. That is, neurons in the posterior part of the inferior frontal gyrus fire when certain

5
click here for more on this important figure in the history of human neuroanatomy.

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 Lateral Surface of the Brain

actions are executed and when those same actions are observed (mirrored) in the behavior of another
individual. Whether these neurons participate in imitation learning—or perhaps even decoding the
intentions of others—remains an area of intense investigation.
Next, let’s cross the lateral fissure. The gyral structure that forms the inferior bank of the lateral fissure
is the superior temporal gyrus. This gyrus is arranged parallel to the lateral fissure and extends from the
anterior pole of the temporal lobe to the parietal lobe (specifically, the angular gyrus of the inferior
parietal lobule). The elongation of this structure in nearly the horizontal plane establishes a framework
for considering the remaining temporal gyral formations of the lateral surface. Including the superior
temporal gyrus, it should be possible to recognize three elongated gyral structures that lie parallel to the
lateral fissure: the superior, middle and inferior temporal gyri. The superior and middle temporal gyri
are separated by the superior temporal sulcus and the middle and inferior gyri are separated by the
inferior temporal sulcus, although the latter sulcus is often discontinuous and sometimes difficult to
recognize.
Notice how the lateral aspects of the frontal and temporal lobes bear some resemblance (at least
conceptually): they both comprise three, parallel longitudinal gyri that extend from the anterior pole of
each lobe back toward the parietal lobe.
Once you are familiar with these gyral features in one specimen, spend some time examining as many
specimens as are available in digital format (a number of free digital resources are available that show
lateral views of the human brain). As you do so, look for differences and common structural themes
among brains and between hemispheres. If you can, carefully examine the pattern and length of the
lateral fissure and consider the following questions.
 Are the two lateral fissures of the same brain roughly the same? If not, how are they different?
 Does the left lateral fissure tend to run mainly in the horizontal plane and extend further posteriorly,
compared to the right lateral fissure?
 Is there an ascending branch of the posterior lateral fissure in the right hemisphere, but not the left?
These questions have been asked and addressed in studies of hemispheric asymmetries and gender
differences related to language lateralization in the human brain. The superior aspect of the temporal
lobe contains the cortical divisions whose functions pertain to audition and the reception of language.
The posterior aspect of the superior temporal gyrus has a special functional name, Wernicke’s Area,
named in recognition of the seminal contributions of the 19th century German physician, Carl
Wernicke6, who described a disturbance of understanding speech, now called Wernicke’s aphasia. You
may find differences in the structure of the superior temporal gyrus in the two hemispheres reflected in
the pattern and length of the lateral fissure; such differences may, in turn, be related to the language
dominance of the left hemisphere. Hemispheric differences in this cortical region may even relate to
musical abilities and other special talents that pertain to audition and semantic encoding.
Other regions of the temporal lobe serve visual processing, emotional processing, memory, and the
integration of sensory experience; we will consider these functions later in the course.
Since you already worked through recognition of the central sulcus, you should now be able to view the
lateral surface of any hemisphere and know to look for the central sulcus lazily coursing from the
longitudinal fissure over the dorsal-lateral surface of the cerebrum in a lateral-ventral and slightly
anterior direction (hopefully, the directional terms applied to the forebrain are also becoming second-
nature to you). Much of the cortex that you observe posterior to the central sulcus is part of the parietal
lobe. The prominent gyral structure that forms the posterior bank of the central sulcus is the postcentral

6
click here for more on this important figure in the history of human neuroanatomy.

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 Lateral Surface of the Brain

gyrus, which is parallel to the precentral gyrus of course. This gyrus is concerned with somatic sensation
and will be a major focus for clinicians concerned with the cerebral localization of touch and body
position sensations. Immediately posterior to the postcentral gyrus is the postcentral sulcus, which
separates the postcentral gyrus from two major gyral formations of the parietal lobe: the superior and
inferior parietal lobules. The boundary between these two lobules is often difficult to appreciate; it is
recognized as a meandering and often discontinuous sulcus called the intraparietal sulcus that tends to
run in a parasagittal plane. We will return to the superior parietal lobule when we explore the medial
surface of the hemisphere.
The gyral formations just inferior to the intraparietal sulcus include the supramarginal gyrus and the
angular gyrus, two principal components of the inferior parietal lobule. The inferior margin of the
parietal lobe is formed mostly by the prominent lateral fissure. However, the posterior limit of the
lateral fissure does not define the entire inferior boundary of the parietal lobe. The supramarginal gyrus
usually forms a “horseshoe” shape around the posterior limit of the lateral fissure, with the angular
gyrus just posterior to the supramarginal gyrus.
Likewise, it is often difficult to discern the boundaries where the posterior parietal and temporal lobes
meet the anterior occipital lobe on the lateral surface of the cerebrum, and it may make no functional
sense to attempt to do so. Nevertheless, we can define an imaginary lateral boundary between the
parietal and occipital lobes in this complex and variable region. Emerging from the depths of the
longitudinal fissure along the medial bank of the cerebral hemisphere (about one-fourth of the length of
the fissure from its posterior limit) is the parieto-occipital sulcus (see Figure A10). We will see this
sulcus more plainly when we explore the medial face of the hemisphere in another tutorial. For now,
appreciate that the parieto-occipital sulcus is the medial boundary between the parietal and occipital
lobes. View the lateral surface of the hemisphere again and carefully inspect its inferior margin. Just
above the cerebellum, there is often a small groove or notch in the gyral structure that can be
appreciated 3-4 cm anterior from the caudal pole of the hemisphere. This groove is called the “pre-
occipital notch” (see Figure A10). Now, draw an imaginary line between the parieto-occipital sulcus
dorsally and the pre-occipital notch ventrally; this line will serve as the lateral boundary between the
parietal and occipital lobes. Simply put, all gyral structures posterior to this line are occipital and have
some role to play in elaborating visual perception. Fortunately for you, the complexity and inter-
individual variation of these gyri defies easy application of standard nomenclature; for this reason, we
will refer to these gyral structures as lateral occipital gyri and leave the business of naming these gyri
for the cortical cartographers.
Lastly, there is a region of cortex called the insula, which is not visible from the lateral surface of the
hemisphere because it is hidden beneath the frontal, temporal, and parietal lobes. The components of
these lobes that cover the insular cortex are often called ‘opercular’ components (‘opercular’ means a
lid or cover). It can be seen if portions of these two lobes are retracted (as is illustrated in Figure A10). In
spite of its name, the insular cortex does not form an island; it is a part of the continuous sheet of cortex
and is deeply buried only because of the relatively greater growth of the cortex around it. Neurons in
the insular cortex are concerned with visceral, autonomic, and taste functions and are thought to
contribute in complex ways to integrative brain functions that impact emotion and social cognition.

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 Lateral Surface of the Brain

STUDY QUESTIONS
Q1. Which of the following statements concerning the central sulcus is most correct?
A. The central sulcus terminates laterally in or very near the longitudinal fissure.
B. The central sulcus is the principal landmark that divides the two cerebral hemispheres
from one another.
C. The central sulcus terminates medially in or very near the lateral (Sylvian) fissure.
D. The central sulcus is formed by gyral formations that harbor the somatic sensory and
motor divisions of the cerebral cortex in the human brain.
E. The central sulcus is mainly in the axial plane of the cranium.

Q2. Which two lobes of the cerebral hemisphere feature three parallel, longitudinal gyri on their
lateral aspect?
A. frontal and temporal lobes
B. frontal and parietal lobes
C. parietal and occipital lobes
D. temporal and occipital lobes
E. temporal and parietal lobes

6
 Medial Surface of the Brain

Medical Neuroscience | Tutorial Notes

Medial Surface of the Brain

MAP TO NEUROSCIENCE CORE CONCEPTS1

NCC1. The brain is the body's most complex organ.

LEARNING OBJECTIVES
After study of the assigned learning materials, the student will:
1. Demonstrate the four paired lobes of the cerebral cortex and describe the boundaries of each.
2. Sketch the major features of each cerebral lobe, as seen from the medial view, identifying major
gyri and sulci that characterize each lobe.

NARRATIVE
by Leonard E. WHITE and Nell B. CANT
Duke Institute for Brain Sciences
Department of Neurobiology
Duke University School of Medicine

Overview
When you view the lateral aspect of a human brain specimen (see Figures A3A and A102), three
structures are usually visible: the cerebral hemispheres, the cerebellum, and part of the brainstem
(although the brainstem is not visible in the specimen photographed in lateral view for Fig. 1 below). The
spinal cord has usually been severed (but we’ll consider the spinal cord later), and the rest of the
subdivisions are hidden from lateral view by the hemispheres. The diencephalon and the rest of the
brainstem are visible on the medial surface of a brain that has been cut in the midsagittal plane. Parts of
all of the subdivisions are also visible from the ventral surface of the whole brain. In this set of tutorials,
you will find video demonstrations (from the brain anatomy lab) and photographs (in the tutorial notes)
of these brain surfaces, and sufficient detail in the narrative to appreciate the overall organization of the
parts of the brain that are visible from each perspective. As you work through this text and if you have
access to an interactive digital atlas of the human brain, such as Sylvius4 Online, find the structures and
regions that are described here3.
The cerebral hemispheres are especially large in humans. They are entirely covered by a 2–3-mm thick
layer of cells and cellular processes called the cerebral cortex. The surface of each hemisphere is highly
1
Visit BrainFacts.org for Neuroscience Core Concepts (©2012 Society for Neuroscience ) that offer fundamental principles
about the brain and nervous system, the most complex living structure known in the universe.
2 th
Figure references to Purves et al., Neuroscience, 5 Ed., Sinauer Assoc., Inc., 2012. [click here]
3
To do so, launch Sylvius4 Online and go to Photographic Atlas, then select one of the atlas filters, such as Gyri, Lobes, or
Sulci and Fissures.

1
 Medial Surface of the Brain

infolded; the ridges thus formed are known as gyri (singular: gyrus) and the valleys are called sulci
(singular: sulcus) or fissures (if they are especially deep). The appearance of the sulci and gyri varies
somewhat from brain to brain. (As you might guess, each one has its own name, but it is necessary to
become familiar with only a few of them.) The hemispheres are conventionally divided into lobes named
for the bones of the skull that overlie them, namely the frontal, parietal, occipital and temporal lobes
(see Figure A3).
Medial aspect of the brain
When the brain is cut in the midsagittal plane, all of its subdivisions are visible on the cut surface (see
Fig. 1 below). Just as in the embryo, the subdivisions are arranged as though they were stacked on top of
one another, with the hemispheres bulging out laterally at the top and the cerebellum bulging out
dorsally and laterally about half-way up the stack. The cerebral hemisphere is still the most prominent
part of the brain in this view.
Beginning from the superior margin of the hemisphere, the most anterior and dorsal gyral formation is
simply the medial continuation of the superior frontal gyrus. A long, almost horizontal sulcus, the
cingulate sulcus, extends across the medial surface of the frontal and parietal lobes just below the
superior frontal gyrus. The prominent gyrus below it, the cingulate gyrus, along with the cortex adjacent
to it, wraps around the corpus callosum and lateral ventricle into the temporal lobe; this extended rim
(Latin, limbus) of cortex is sometimes called the ‘limbic lobe’. These cortical areas—and the subcortical
areas connected to them, together with additional telencephalic structures in the temporal lobe and
ventral frontal lobe—are often referred to as the ‘limbic system’. However, this so-called system (so-
called primarily for historical reasons) is not unimodal, as the term ‘system’ implies. Rather, the limbic
‘system’ is involved in the regulation of visceral
motor activity, emotional experience and Many authors now advocate dismissal of the term
expression, olfaction, and memory, to name some “limbic system” as an outmoded and misleading
of its better understood functions (see tutorial on concept, and rather emphasize the diverse functions
associated with the various components of
The Amygdala and Hippocampus for more expansive networks in the ventral-medial forebrain.
information on the anatomy of the limbic
forebrain).
The caudal portion of the superior frontal gyrus forms the paracentral lobule, as it joins the medial
continuation of the pre- and post-central gyri. Just as on the lateral surface of the hemisphere, on the
medial face of the hemisphere the frontal lobe extends from the central sulcus forward. At the inferior
margin of the frontal lobe is the medial aspect of an inferior gyrus called the gyrus rectus (see ‘ventral
view’ below), and a small cortical division, called the subcallosal area, just below the genu (“knee”) of
the corpus callosum. This subcallosal area has become an important target for deep brain stimulation in
the treatment of various psychiatric diagnoses, including major depressive disorder.
Locate again the medial terminus of the central sulcus in the paracentral lobule. That sulcus marks the
anterior boundary of the parietal lobe, at least its dorsal portion; the rest of the anterior boundary
follows the posterior limit of the cingulate gyrus. Now, about half-way between the central sulcus and
the posterior pole of the hemisphere, note the presence of a prominent sulcus running in nearly the
coronal plane (actually, it is usually angled posteriorly from its inferior to superior ends) (see Figure A3B
and A12). This sulcus is the parieto-occipital sulcus and it divides the parietal and occipital lobes. The
entire gyral formation visible in this view of the parietal lobe is called the precuneus gyrus (its name will
make sense as you read on).
Now, consider the brain from its dorsal surface. Can you now appreciate where the parieto-occipital
sulcus intersects the longitudinal fissure? In the dorsal view, there is often a rather prominent furrow

2
 Medial Surface of the Brain

where this sulcus widens at the dorsal midline. Keep the location of that intersection in mind; cortex
posterior to this location is part of the occipital lobe (as our exploration of the medial parietal surface
should make clear) and the gyral formation between this intersection and the central sulcus is, of
course, the parietal lobe. By convention, much of the parietal lobe visible in the dorsal view, excluding
the postcentral gyrus, is called the superior parietal lobule, which is a continuation of the precuneus
gyrus onto the dorsal-lateral surface of the hemisphere.
So much for a brief consideration of the dorsal view of the brain; let’s return to the medial (midsagittal)
surface and consider the posterior aspect of the hemisphere.

To appreciate the medial parietal and occipital lobes, reorient yourself to the parieto-occipital sulcus
(see Figure A12). Next, recognize the calcarine sulcus, which intersects the parieto-occipital sulcus at
nearly a right angle and extends typically to the occipital pole of the hemisphere. We’ll come back to this
part of the brain when we study the visual system. For now, notice the “tongue”-like gyral structure that
forms the inferior bank of the calcarine sulcus, and the “wedge”-shaped gyrus that forms its superior
bank. Thankfully, the formal terms for these gyri mean just that:
 Lingual gyrus; “lingual” (Latin, lingua) means “tongue”
 Cuneus gyrus; “cuneus” (Latin, cuneus) means “wedge”
The precuneus gyrus, of course, lies just in front of (anterior to) the cuneus gyrus. Note that the
precuneus gyrus is really a medial extension of the superior parietal lobule. But on the medial face of the
hemisphere, we call this the precuneus gyrus (which you can now remember as the gyrus in front of the
“wedge”).
The occipital lobe serves vision. The cortex in the banks of the calcarine sulcus is the first division of the
occipital lobe to receive information derived from the retinas (relayed via the thalamus); hence it is
called the primary visual cortex (also called the “striate cortex” because of a conspicuous stripe or
striation that runs through the middle of the cortex in the banks of the calcarine sulcus). Damage to this
part of the occipital lobe can result in blindness for some portion of the visual field. Surrounding
occipital regions—and posterior parts of the parietal and temporal lobe—process increasingly more
complex aspects of vision (e.g., the location, color, form and motion of objects, and recognition of their
identity). Localized injury or disease affecting one of these “higher-order” or associational visual areas
can result in remarkably specific impairments of visual function, such as the inability to appreciate
motion or recognize a familiar face (more on such visual functions in later class sessions).
Three prominent fiber bundles (i.e., bundles of axons extending from one part of the brain to another)
associated with the cerebral hemispheres can be seen from the medial view (see Figure A12 and Fig. 1
below). These are:
1. the corpus callosum, a huge structure that contains 100s of millions of axons and connects the
cortices of the two hemispheres, except for cortex in the anterior temporal and ventral (orbital)
frontal lobes;
2. the anterior commissure, a much smaller bundle of axons that connects cortex in the anterior
temporal and ventral frontal lobes, in addition to other ventral telencephalic structures; and
3. the fornix, a large fiber bundle that connects the hippocampus (a part of the temporal lobe that
you haven’t seen yet) with the hypothalamus and related ventral, midline structures.

3
 Medial Surface of the Brain

In the view shown in Fig. 1, the axons in the corpus callosum and anterior commissure are running
perpendicular to the plane of the page, and the visible fibers of the fornix are running within the plane
of the page.
The other subdivisions of the brain, all of which can be seen in Fig. 1 (labeled in Figure A12), are as
follows:
1. The diencephalon consists of four parts arrayed from dorsal to ventral. A. The epithalamus is a
small strip of tissue to which is attached the pineal gland. B. The thalamus, the largest part,
relays most of the information going into the cortex from other parts of the brain and spinal
cord. The thalamus consists of many further subdivisions, some of which you will learn about in
later tutorials. C. The subthalamus, a small area concerned with control of motor and cognitive
functions, cannot be seen from this view since it does not extend all the way to the midline (this
small diencephalic region is a frequent target of deep brain stimulation for control of movement
disorders). D. The hypothalamus, a small but crucial part of the brain, is devoted to the control
of homeostasis and a rich variety of physiological activities that are essential for survival and
reproduction. It is bounded rostrally by the optic chiasm, and its caudal extremity is made up of
swellings known as the mammillary bodies. On some brain specimens, the pituitary gland or part
of its stalk (the infundibulum) may still be attached to the ventral surface of the hypothalamus.
2. The mesencephalon or midbrain lies just caudal to the thalamus. Prominent landmarks that can
be seen on the dorsal surface of the midbrain are the superior and inferior colliculi. They are
concerned with oculomotor function and postural adjustments (superior colliculi) and audition
(inferior colliculi). The other prominent external feature of the midbrain, the cerebral peduncles,
cannot be seen very well from this view as they do not quite reach the midline (we will return to
them in another tutorial).
3. The pons is next as we proceed caudally. It would be difficult to miss the pons because of the
massive enlargement on its ventral surface. (Pons means ‘bridge’; the enlargement is made up
of cells with transversely oriented axons that cross the midline and could be said to form a
bridge across the base of the brainstem.) A further feature that identifies the pons is its
attachment to the cerebellum which lies dorsal to it. The cerebellum plays a crucial role in the
coordination of movement.
4. Finally, the most caudal subdivision of the brainstem is the medulla oblongata (or “medulla” for
short). From the medial view shown in Fig. 1, it looks relatively featureless. We will explore its
external landmarks further on the ventral view of the brain in another tutorial.

4
 Medial Surface of the Brain

Fig 1. Medial surface of the hemisected human brain. This figure is not labeled so that you may refer to
it for review; see Figure A12 for illustrated and labeled views of the same hemisphere. (Image from
Sylvius4 Online)

All components of the ventricular system, except perhaps for the lateral ventricles, can be seen on a
typical medial surface of the brain cut in the midsagittal plane. In Fig. 1, the lateral ventricle is visible in
this hemisphere because the septum pellucidum has been dissected away; this is a very thin layer of
tissue that forms the medial wall separating the two lateral ventricles. The third ventricle forms a
narrow space in the midline region of the diencephalon, between the one that you see and the one that
has been cut away. The communication of the third ventricle with the lateral ventricle is through a small
hole, the interventricular foramen (or foramen of Monroe), at the anterior-dorsal end of the third
ventricle. The third ventricle is continuous caudally with the cerebral aqueduct which runs through the
midbrain. At its caudal end, it joins the fourth ventricle, a large space in the dorsal pons and medulla.
The fourth ventricle narrows caudally to join the central canal. We will take a closer look at the
ventricles when we inspect cross-sections through the forebrain in a later tutorial.

5
 Medial Surface of the Brain

STUDY QUESTIONS
Q1. Which of the following external spaces provides a major landmark dividing one cerebral lobe
from another?
A. superior frontal sulcus
B. parieto-occipital sulcus
C. calcarine sulcus
D. cingulate sulcus
E. lateral (Sylvian) fissure

Q2. Which of the following pairs of terms identify spaces that are roughly PERPENDICULAR
(orthogonal) in the human brain (give or take 30 degrees or so)?
A. calcarine sulcus and central sulcus
B. precentral sulcus and postcentral sulcus
C. superior temporal sulcus and inferior temporal sulcus
D. superior frontal sulcus and intraparietal sulcus
E. central sulcus and the parieto-occipital sulcus

6
 Finding the Central Sulcus

Medical Neuroscience | Tutorial Notes

Finding the Central Sulcus

MAP TO NEUROSCIENCE CORE CONCEPTS1

NCC1. The brain is the body's most complex organ.

LEARNING OBJECTIVES
After study of the assigned learning materials, the student will:
1. Recognize the central sulcus from its medial terminus in the paracentral lobule to its lateral
terminus in the lateral fissure.
2. Sketch the central sulcus in the cerebral hemisphere and label the segments of the pre- and
post-central gyri that represent somatic motor control and somatic sensation for the
contralateral leg, arm and face.

NARRATIVE
by Leonard E. WHITE and Nell B. CANT
Duke Institute for Brain Sciences
Department of Neurobiology
Duke University School of Medicine

Overview
When you view the lateral aspect of a human brain specimen (see Figures A3A and A102), three
structures are usually visible: the cerebral hemispheres, the cerebellum, and part of the brainstem
(although the brainstem is not visible in the specimen photographed in lateral view for Fig. 1 below). The
spinal cord has usually been severed (but we’ll consider the spinal cord later), and the rest of the
subdivisions are hidden from lateral view by the hemispheres. The diencephalon and the rest of the
brainstem are visible on the medial surface of a brain that has been cut in the midsagittal plane. Parts of
all of the subdivisions are also visible from the ventral surface of the whole brain. Over the next several
tutorials, you will find video demonstrations (from the brain anatomy lab) and photographs (in the
tutorial notes) of these brain surfaces, and sufficient detail in the narrative to appreciate the overall
organization of the parts of the brain that are visible from each perspective. As you work through this
text and if you have access to an interactive digital atlas of the human brain, such as Sylvius4 Online,
find the structures and regions that are described here3.

1
Visit BrainFacts.org for Neuroscience Core Concepts (©2012 Society for Neuroscience ) that offer fundamental principles
about the brain and nervous system, the most complex living structure known in the universe.
2 th
Figure references to Purves et al., Neuroscience, 5 Ed., Sinauer Assoc., Inc., 2012. [click here]
3
To do so, launch Sylvius4 Online and go to Photographic Atlas, then select one of the atlas filters, such as Gyri, Lobes, or
Sulci and Fissures.

1
 Finding the Central Sulcus

The cerebral hemispheres are especially large in humans. They are entirely covered by a 2–3-mm thick
layer of cells and cellular processes called the cerebral cortex. The surface of each hemisphere is highly
infolded; the ridges thus formed are known as gyri (singular: gyrus) and the valleys are called sulci
(singular: sulcus) or fissures (if they are especially deep). The appearance of the sulci and gyri varies
somewhat from brain to brain. (As you might guess, each one has its own name, but it is necessary to
become familiar with only a few of them.) The hemispheres are conventionally divided into lobes named
for the bones of the skull that overlie them, namely the frontal, parietal, occipital and temporal lobes
(see Figure A3).
Lateral aspect of the brain
The central sulcus is one of the most important landmarks in the human brain for clinicians and
neuroscientists because it precisely divides the somatic sensory cortex of the parietal lobe from the
motor cortex of the frontal lobe. An appreciation of the structure of the central sulcus—actually, the
structure of the gyri that form the central sulcus—will help you understand how the opposite side of the
body is represented in the somatic sensory and motor areas that reside in these gyral formations.
Surprisingly, the most reliable way to find the central sulcus is not by inspecting the lateral surface of the
brain, where this is one of the longest and deepest sulci of the human cerebral cortex. Rather, the best
way to find the central sulcus is to start on the medial surface of the hemisphere. So refer to Fig. 1 below
(see also Figure A12) or view the medial surface of the brain using Sylvius4 Onine and locate the
cingulate sulcus on the medial surface of the hemisphere. Follow this posteriorly to its marginal ramus,
a sharp turn in the sulcus where it ascends to the top of the hemisphere. The sulcus just anterior to the
marginal ramus (on the dorsal-lateral surface of the hemisphere) is the central sulcus.
To be certain that the first sulcus anterior to the marginal branch of the cingulate sulcus is the central
sulcus, follow the course of the sulcus that you just identified as the central sulcus and you should see
that it courses along the lateral surface in a gentle anterior progression as you trace it from the dorsal
midline toward its inferior margin (see Fig. 2 below; see also Figure A10). Along the way, note the lazy
“S”-shaped bend it takes near the middle of the cerebral hemisphere. With remarkable consistency, that
is where the somatic sensory and motor representations of the contralateral arm and hand are localized.
The gyral structure bounded by the marginal branch of the cingulate sulcus on the dorsal midline of the
hemisphere is also important; this structure, named the paracentral lobule, contains the somatic
sensory and motor representations of the contralateral foot. So where’s the face represented? Here’s
another surprise—the contralateral face is localized to the inferior segment of the central sulcus below
that lazy “S” shape (not where you might expect it, if the body where mapped contiguously). As you take
all of this in, remember: in each of these segments, somatic sensation is represented on the posterior or
parietal side of the central sulcus (in the postcentral gyrus) and motor control is localized to the anterior
or frontal side of the sulcus (in the precentral gyrus).
If you have access to Sylvius4 Online, open the Unlabeled image set in the Sectional Anatomy group and
view the most dorsal horizontal (axial) section in the set. At this level and plane, the central sulcus is
usually the deepest sulcus near the middle of the hemisphere. If you don’t have Sylvius4, then refer to
Fig. 3 below, which shows a similar plane of section in a T1-weighted MR image. In either section, notice
that in the depths of the central sulcus, there should also be a conspicuous Ω shape (i.e., “omega-
shape”) formed by an interdigitation of the sulcal walls. This gyral feature is what accounts for the “S”
shape that can be appreciated when the central sulcus is viewed from the dorsal-lateral surface of the
hemisphere. More importantly, the somatic motor and sensory representation of the contralateral hand
invariably includes this distinctive Ω-shape deep in the central sulcus. Evidently, this morphological
feature reflects the “over-representation” of the hand in the human brain and the instantiation of this

2
 Finding the Central Sulcus

important functional representation with as much cortical structure as can be packaged into a cramped
space. The Ω-shape (which is sometimes called the “hand knob” by neurologists and neuroradiologists)
is mainly attributed to a posterior outgrowth of the precentral gyrus, which harbors the primary motor
cortex.

Fig. 1. Medial surface of the hemisected human brain. This figure is not labeled so that you may refer to
it for review; see Figure A12 for illustrated and labeled views of the same hemisphere. (Image from
Sylvius4 Onilne)

3
 Finding the Central Sulcus

Fig. 2. Lateral surface of the human brain. This figure is not labeled so that you may refer to it for review; see
Figures A3 & A10 for an illustrated and labeled view of the same hemisphere. The asterisk marks the lazy “S”-
shaped bend in the central sulcus near the middle of the cerebral hemisphere. (Image from Sylvius4 Online)

4
 Finding the Central Sulcus

Fig. 3. Axial image through the forebrain

acquired with T1-weighted MR imaging
(anterior is toward the top). The red arrows
identify the central sulcus. (Image from
Sylvius4 Online)

STUDY QUESTIONS
Which of the following statements concerning the central sulcus is most correct?
A. The central sulcus terminates laterally in or very near the longitudinal fissure.
B. The central sulcus terminates medially in or very near the lateral (Sylvian) fissure.
C. The central sulcus by gyral formations that harbor the primary visual cortex in the human brain.
D. The central sulcus is formed by the growth and morphogenesis of the cuneus gyrus and the
lingual gyrus of the cerebral cortex in the human brain.
E. The central sulcus is formed by the growth and morphogenesis of the precentral gyrus and the
postcentral gyrus of the cerebral cortex in the human brain.

5
 Ventral Surface of the Brain

Medical Neuroscience | Tutorial Notes

Ventral Surface of the Brain

MAP TO NEUROSCIENCE CORE CONCEPTS1

NCC1. The brain is the body's most complex organ.

LEARNING OBJECTIVES
After study of the assigned learning materials, the student will:
1. Describe the major features of the cerebral lobes, as seen from the ventral view, discussing
major gyri and sulci that characterize each lobe.
2. Recognize the major embryological subdivisions of the brain that are visible from the ventral
view.

NARRATIVE
by Leonard E. WHITE and Nell B. CANT
Duke Institute for Brain Sciences
Department of Neurobiology
Duke University School of Medicine

Overview
When you view the lateral aspect of a human brain specimen (see Figures A3A and A112), three
structures are usually visible: the cerebral hemispheres, the cerebellum, and part of the brainstem
(although the brainstem is not visible in the specimen photographed in lateral view for Fig. 1 below). The
spinal cord has usually been severed (but we’ll consider the spinal cord later), and the rest of the
subdivisions are hidden from lateral view by the hemispheres. The diencephalon and the rest of the
brainstem are visible on the medial surface of a brain that has been cut in the midsagittal plane. Parts of
all of the subdivisions are also visible from the ventral surface of the whole brain. In this set of tutorials,
you will find video demonstrations (from the brain anatomy lab) and photographs (in the tutorial notes)
of these brain surfaces, and sufficient detail in the narrative to appreciate the overall organization of the
parts of the brain that are visible from each perspective. As you work through this text and if you have
access to an interactive digital atlas of the human brain, such as Sylvius4 Online, find the structures and
regions that are described here3.
The cerebral hemispheres are especially large in humans. They are entirely covered by a 2–3-mm thick

1
Visit BrainFacts.org for Neuroscience Core Concepts (©2012 Society for Neuroscience ) that offer fundamental principles
about the brain and nervous system, the most complex living structure known in the universe.
2 th
Figure references to Purves et al., Neuroscience, 5 Ed., Sinauer Assoc., Inc., 2012. [click here]
3
To do so, launch Sylvius4 Online and go to Photographic Atlas, then select one of the atlas filters, such as Gyri, Lobes, or
Sulci and Fissures.

1
 Ventral Surface of the Brain

layer of cells and cellular processes called the cerebral cortex. The surface of each hemisphere is highly
infolded; the ridges thus formed are known as gyri (singular: gyrus) and the valleys are called sulci
(singular: sulcus) or fissures (if they are especially deep). The appearance of the sulci and gyri varies
somewhat from brain to brain. (As you might guess, each one has its own name, but it is necessary to
become familiar with only a few of them.) The hemispheres are conventionally divided into lobes named
for the bones of the skull that overlie them, namely the frontal, parietal, occipital and temporal lobes
(see Figure A3).

If it were possible to unfold the cerebral cortex from one hemisphere (which can be
done in digital representations of the cerebral hemisphere), the surface area of the
resulting, flattened cerebral cortex would be roughly approximated by the crust of a
13-inch pizza (thin crust, New York style, of course, given the thinness of the cortex).

Ventral aspect of the brain

Fig. 1 below provides another look at the surface of the whole brain (see also Figure A11). Most of the
subdivisions of the brain can be seen when it is viewed from its ventral aspect. The inferior surfaces of
the frontal and temporal lobes of the cerebral hemispheres are prominent in this view. Running along
the inferior surface of the frontal lobe near the midline are the olfactory tracts, which arise in little
swellings at their anterior ends, the olfactory bulbs. The olfactory bulbs receive the axons of sensory
cells in the olfactory mucosa (these axons are the first cranial nerve), and neurons in the bulbs give rise
to fibers in the olfactory tracts (therefore, the tracts are part of the forebrain). Just superior to the
bulbs, of course, is the ventral aspect of the frontal lobe, often referred to as the “orbital cortex” since
this is the portion of the frontal lobe the overlies the orbits. The olfactory bulbs and tracts lie in the
olfactory sulci (one in each hemisphere). This sulcus divides the gyrus rectus at the medial margin of the
ventral frontal lobe from the more complex gyral structures that occupy much of the remaining ventral
aspect; we will refer to these gyri simply as orbital gyri. Most of the ventral aspect of the frontal lobe is
visible in Fig. 1, except for that posterior portion hidden by the underlying anterior temporal lobes.
On the ventral surface of the temporal lobe, the inferior temporal gyrus occupies most of the visible
surface of the lobe (with brainstem and cerebellum intact). However, it is possible to appreciate
additional gyral structures on the medial side of the ventral temporal lobe. The medial boundary of the
inferior temporal gyrus is formed by two sulci, the rhinal sulcus more anteriorly and the collateral sulcus
more posteriorly. Just on the medial side of these sulci are gyral structures that are associated with the
hippocampal formation (a primitive cortical structure that we will see when we dissect the brain); first,
is the parahippocampal gyrus and then a medial protuberance of this gyrus called the uncus. Just
posterior to the parahippocampal gyrus is another prominent structure called the occipito-temporal
gyrus (also called—especially by functional brain imagers—the fusiform gyrus), but this gyrus is mostly
hidden from view in Fig. 1 by the cerebellum.
A small part of the diencephalon is visible in this view of the brain. The part that you see is the
hypothalamus, bounded rostrally by the optic chiasm (formed by the crossing of some of the axons in
cranial nerve II) and caudally by the mammillary bodies, which are considered part of the hypothalamus.
The midbrain is mostly hidden from view by the temporal lobes; however, the prominent paired
cerebral peduncles are visible (these structures define a space between them called the interpeduncular
fossa).
The pons is obvious in this view, as are the middle cerebellar peduncles, which attach the pons to the
cerebellum. Cranial nerve V (the trigeminal nerve), the largest of the cranial nerves, arises at the level of

2
 Ventral Surface of the Brain

the pons. Caudal to the pons is the medulla. The columnar swellings on its ventral surface on either side
of the midline are known as the medullary pyramids. They contain axons that arise in the precentral
(the motor cortex) and the postcentral gyri (the somatic sensory cortex) and terminate in the spinal cord
(i.e., the corticospinal tract) and medulla (a portion of the corticobulbar tract). Lateral to the pyramids
are the inferior olives. Caudal to the medulla, a portion of the cervical spinal cord is seen. Cranial nerves
VI-XII arise from the medulla or at the junction of the pons and medulla. We will consider them in detail
later, when we discuss more comprehensively the brainstem and its relation to the cranial nerves (see
the tutorial, Surface Anatomy of the Brainstem).

Fig. 1. The ventral surface of the brain. (Image from Sylvius4 Online)

3
 Ventral Surface of the Brain

STUDY QUESTION
Which of the following structures is hidden from view when the brain is seen from its ventral surface?
A. midbrain
B. hypothalamus
C. corpus callosum
D. medullary pyramids
E. cerebral peduncles

4
 Blood Supply to the Brain

Medical Neuroscience | Tutorial Notes

Blood Supply to the Brain

MAP TO NEUROSCIENCE CORE CONCEPTS1

NCC1. The brain is the body's most complex organ.

LEARNING OBJECTIVES
After study of the assigned learning materials, the student will:
1. Identify the major blood vessels that comprise the anterior and posterior circulation of the
brain.
2. Discuss the source of blood to the anterior and posterior circulation.
3. Sketch the anastomotic ring of blood vessels (the circle of Willis) at the base of the brain.
4. Identify the major blood vessels that supply the spinal cord.
5. Describe the system of vessels for venous drainage of blood from the brain into the jugular
veins.

NARRATIVE
by Leonard E. WHITE and Nell B. CANT
Duke Institute for Brain Sciences
Department of Neurobiology
Duke University School of Medicine

Overview of the anterior and posterior circulation

This tutorial contains a brief overview of the distribution of blood supply to each subdivision of the brain
and to the spinal cord. Lesions involving the different vessels and their branches lead to specific
syndromes that are easy to understand if you learn the distribution patterns of the vessels and the
organization of the brain and spinal cord subdivisions that they supply.
The brain receives its arterial supply from two sources: the internal carotid arteries and the
vertebral/basilar arteries (the two vertebral arteries join to form the basilar artery at the base of the
pons). Both the internal carotid arteries and the vertebral/basilar arteries give rise to four main
branches, commonly referred to as the anterior circulation and the posterior circulation, as depicted in
the chart (next page; see also Figures A15 & A162. This chart accounts for the major branches of the
carotid and vertebral/basilar arteries. The two systems of arteries are joined at the junction between

1
Visit BrainFacts.org for Neuroscience Core Concepts (©2012 Society for Neuroscience ) that offer fundamental principles
about the brain and nervous system, the most complex living structure known in the universe.
2 th
Figure references to Purves et al., Neuroscience, 5 Ed., Sinauer Assoc., Inc., 2012. [click here]

1
 Blood Supply to the Brain

the posterior communicating artery and the posterior cerebral artery. In most humans, the posterior
cerebral artery receives its blood supply from the vertebral/basilar system. In some people, the
posterior communicating artery is quite large, and the posterior cerebral artery may be perfused
significantly by the carotid artery.
Generally speaking, the anterior circulation supplies the forebrain (the cerebral hemispheres and the
diencephalon), and the posterior circulation supplies the brainstem and the upper spinal cord. However,
for most people, the arterial supply to the CNS is not quite that simple. As just mentioned, the posterior
cerebral artery supplies the posterior forebrain, including some deep structures, and it also supplies
parts of the midbrain in the brainstem. Thus, as indicated in the chart (by listing the posterior cerebral
artery twice, once in each group), the posterior cerebral artery contributes to both the anterior and
posterior circulations. As you study this tutorial, you should learn the distributions of these 8 arteries
listed in this chart.

Supply Cerebral artery Group

1. Anterior cerebral artery
2. Middle cerebral artery
Internal carotid 3. Anterior choroidal artery Anterior circulation
4. Posterior communicating artery
5. Posterior cerebral artery
5. Posterior cerebral artery
6. Superior cerebellar artery
Vertebral / Basilar Posterior circulation
7. Anterior inferior cerebellar artery
8. Posterior inferior cerebellar artery

The anterior circulation

The four major arteries that arise from the internal carotid artery plus the posterior cerebral artery
form the anterior circulation. The pattern of branching of each artery is similar: each gives rise to
branches that supply cortical structures and each gives rise to branches that penetrate the ventral
surface of the brain and supply deep structures (the basal ganglia, thalamus and internal capsule), as
illustrated in the Figures A17 & A18. (The branches that supply deep structures are known collectively as
perforating arteries, central arteries, striate arteries, or ganglionic arteries.)
An extensive region of the central and lateral cerebral hemispheres is supplied by the middle cerebral
artery (green shade in Figure A18). Included in this region are the sensorimotor areas that govern the
upper extremities and face, and the language areas of the left hemisphere (Broca’s area and Wernicke’s
area). The anterior cerebral artery supplies regions in the medial aspect and dorsal and orbital margins
of the frontal lobe, and the medial aspect and dorsal margin of the anterior parietal lobe (yellow shade
in Figure A18). Included in this extended territory are sensorimotor areas in the paracentral lobule that
govern the lower extremity, accessory motor areas in the cingulate gyrus that govern the upper face
(see Box 17A in Neuroscience, 5th Ed.), and limbic areas in the medial frontal lobe. The posterior cerebral
artery supplies regions in the posterior parietal lobe, inferior temporal lobe and occipital lobe (blue
shade in Figure A18). Included in this region are primary and associational (higher-order) visual areas in
each lobe and ‘limbic’ regions in the posterior cingulate and parahippocampal gyri.

2
 Blood Supply to the Brain

At this point, you should recognize that this tutorial on blood supply affords the opportunity to review
what you have already learned regarding the localization of function in the cerebral cortex. One of the
main goals of this course is to understand the functional consequences of injury to various structures in
the human central nervous system. One of the most prevalent forms of brain injury is attributable to
cerebral vascular disease (i.e., cerebral vascular accident or stroke). To prepare you for considering
clinical cases involving stroke (which we will do later in the course), work to become thoroughly familiar
with the distributions of the major cerebral arteries relative to the cerebral cortex. Refer back to
previous tutorials and review as many of the specific functional areas of the cerebral cortex as were
identified (note the bold terms, including Broca’s and Wernicke’s areas). More generally, as you study
the distribution of the cerebral vessels and what you now know about the four lobes of the cerebral
cortex, see if you can predict what kinds of neurological signs and symptoms might result from stroke
involving the right or left anterior, middle or posterior cerebral arteries.
Each of the four major branches of the internal carotid artery give rise to penetrating branches, in
addition to the superficial branches just described, that supply gray and white matter structures deeper
in each hemisphere. These deep branches follow a reasonably straight-forward, anterior-to-posterior
pattern of branching (see Figure A18). We will introduce the deep structures of the cerebral
hemispheres in a later tutorial; here, you should simply learn the basic pattern of deep supply outlined
below. The anterior cerebral artery supplies the anterior caudate and putamen, the nucleus accumbens,
and the anterior limb of the internal capsule—all structures in the anterior deep forebrain. The middle
cerebral artery supplies the body of the caudate and most of the putamen, most of the globus pallidus,
the middle part (or genu) of the internal capsule, and the anterior hypothalamus—all structures near
the middle of the deep forebrain. These deep penetrating branches of the middle cerebral artery are
usually called the lenticulostriate arteries (see Figure A18). The anterior choroidal artery supplies the
amygdala, hippocampus, the anterior part of the thalamus, part of the globus pallidus, the posterior
limb of the internal capsule, and the choroid plexus of the lateral ventricle—all structures that are also
in middle of the deep forebrain, but mainly just posterior to the distribution of the lenticulostriate
arteries. Lastly, the posterior communicating and posterior cerebral arteries supply the posterior
hypothalamus, most of the thalamus, and the choroid plexus of the third ventricle—all structures in the
posterior deep forebrain. (Branches of the posterior cerebral artery also supply the midbrain as
described later.)
The good news is that it is not necessary to remember all of these details! You should, however, know
the arteries in bold font above, and you should remember that the deep structures of the forebrain are
divided approximately into four sectors progressing from anterior to posterior, and each sector is
perfused by a different artery.

The posterior circulation

The pattern of arterial distribution is similar in all three subdivisions of the brainstem, as illustrated
schematically in Fig. 1 below. The specific pattern in each subdivision is shown in Neuroscience, 5th Ed.,
Figure A19.
The brainstem blood supply can be loosely divided into median and paramedian perforating arteries,
lateral perforating arteries and dorsal perforating arteries. The vertebral and basilar arteries and their
four major branches give rise to these perforating arteries. As their names imply, the three cerebellar
arteries also supply the cerebellum.
Each of the three subdivisions of the brainstem can be divided into medial and lateral ‘wedges’ of tissue
that are supplied by different perforating branches. Vascular lesions that affect individual wedges of

3
 Blood Supply to the Brain

brainstem tissue lead to distinct neurological syndromes, as you will study later in this course in the
context of understanding the organization of long pathways in the brainstem and the distribution of
cranial nerve nuclei. For now, note that most vascular lesions of the brainstem are usually unilateral,
since each side of the brainstem is supplied by different sets of circumferential vessels. However, this
may not be true if the basilar artery itself is blocked, since it gives rise to vessels that supply both sides.

Fig. 1. The basic plan of blood supply to the brainstem. The major vessel on the ventral surface of the brainstem
gives rise t0:
1. median and paramedian perforating arteries
2. lateral perforating arteries (short circumferential arteries)
3. dorsal perforating arteries (long circumferential arteries)

Drainage of venous blood

Figure A15A (Neuroscience, 5th Ed.) illustrates the system of veins that provides for the drainage of
venous blood from the brain and cranium. This figure provides an overview of the means by which blood
completes its passage through the brain from the arterial vasculature back to the heart via the internal
jugular veins. In brief, the more superificial veins of the cerebrum drain into the superior sagittal sinus
along the dorsal midline of the hemisphere, or the cavernous sinus in the base of the cranium. The
deeper veins of the brain drain into the inferior sagittal sinus at the inferior margin of the falx cerebri,
and the great vein of Galen, which in turn join to form the straight sinus. The major venous sinuses
inside the cranium are formed by a separation of the two layers of dura mater. The superior sagittal
sinus and the straight sinus drain into a pair of transverse sinuses, which are oriented roughly in the
horizontal plane along the posterior margin of the tentorium. The transverse sinuses then turn in the
inferior direction, becoming the sigmoid sinuses, which finally exit the cranial vault as the internal
jugular veins.

4
 Blood Supply to the Brain

The arterial supply of the spinal cord

The arterial blood that supplies the spinal cord comes from two sources: the vertebral arteries (and/or
posterior inferior cerebellar arteries) and segmental arteries that arise from branches of the aorta.
These arteries join the anterior and posterior spinal arteries (as illustrated in Figure A16). At the level of
the medulla, the vertebral arteries give off branches that merge to form the single anterior spinal artery.
Approximately 10 segmental arteries (that arise from various branches of the aorta) join the anterior
spinal artery along its course. These segmental arteries are known as medullary arteries. [Other
segmental arteries supply the dorsal root ganglia but do not join the spinal artery; these are known as
radicular arteries]. It is important to realize that if any of the medullary arteries are obstructed or
damaged, blood supply to part of the spinal cord may be compromised and neurological damage will
result. The pattern of damage depends on whether the supply to the posterior arteries or anterior artery
is interrupted. An anastomotic network of vessels known as the vasocorona connects these two sources
of supply and sends branches into a narrow zone of white matter around the margin of the spinal cord.
The vasocorona may be sufficient to supply the most lateral white matter in cases in which the anterior
spinal artery is occluded. The anterior spinal artery gives rise to about 200 sulcal arteries that branch to
supply the anterior two-thirds of the spinal cord. Thus, the anterior spinal artery supplies the ventral
horn and the surrounding ventral and lateral columns of white matter.
The vertebral arteries (or the posterior inferior cerebellar artery) also give rise to paired posterior spinal
arteries that run along the dorsal (posterior) surface of the spinal cord. As for the anterior spinal artery,
medullary arteries supply the posterior spinal artery (actually an anastomotic network of arteries) along
its length. The posterior spinal artery gives rise to branches that penetrate the posterior one-third of the
spinal cord and so supply much of the dorsal horn and the dorsal columns.

STUDY QUESTIONS
Q1. A patient presents with “foot drop”, meaning that when the person walks, one foot is “floppy”
requiring exaggerated movements to compensate for weak ankle dorsiflexion during
ambulation. (There were no other major complaints or impairments.) There are different
possible etiologies for this particular neurological dysfunction, including peripheral neuropathy.
However, you should also consider a stroke involving blood supply to the cerebral cortex.
Of the possible stroke syndromes attributable to major cerebral arteries, which one is most
likely to give this patient foot drop?
A. anterior choroidal artery
B. middle cerebral artery
C. posterior cerebral artery
D. anterior cerebral artery
E. vertebral artery
Q2. The supply of blood to the spinal cord is derived from which vessels?
A. the vertebral arteries only
B. medullary (segmental) arteries only
C. posterior inferior cerebellar arteries only
D. radicular arteries only
E. medullary (segmental) arteries and vertebral arteries

5
 Cranial and Spinal Nerves

Medical Neuroscience | Tutorial Notes

Cranial and Spinal Nerves

MAP TO NEUROSCIENCE CORE CONCEPTS1

NCC1. The brain is the body's most complex organ.

LEARNING OBJECTIVES
After study of the assigned learning materials, the student will:
1. Discuss the functions of the cranial nerves in terms of the sensory and motor signals conveyed
by each nerve.
2. Discuss the organization and composition of a typical spinal nerve.

NARRATIVE
by Leonard E. White and Nell B. Cant
Duke Institute for Brain Sciences
Department of Neurobiology
Duke University School of Medicine

Introduction
After working through this tutorial, you should be able to discuss the composition and function of the
cranial nerves, and you should be able to discuss the general organization of spinal nerves. In the next
tutorial, you will learn how the cranial nerves relate to gray matter structures in the brainstem that grew
out the axons in the cranial nerves (motor axons) or receive synaptic input from ganglionic neurons
associated with the nerves (sensory axons). But before proceeding, you should make sure that you
understand the basic layout of sensory and motor neurons in the brainstem and spinal cord.
The central nervous system interacts with the outside world through primary sensory neurons, which
convey information from the body or its environment into the brain and spinal cord, and motor neurons,
which activate striated muscles and modulate the activity of cardiac and smooth muscles and glands
(see Fig. 1 below and/or Figure A1A2). The cell bodies of primary sensory neurons lie in the dorsal root
ganglia or the cranial nerve ganglia. Each neuron gives rise to a peripheral process, which receives
information either directly or through association with receptors, and a central process, which enters
the central nervous system and forms synapses with second order neurons. The cell bodies of somatic
motor neurons lie in clusters or nuclei within the central nervous system and give rise to axons that
innervate striated muscles in the body or head. You will also be introduced to other motor neurons that
are part of the visceral motor system (a.k.a., autonomic nervous system) and are indirectly responsible
1
Visit BrainFacts.org for Neuroscience Core Concepts (©2012 Society for Neuroscience ) that offer fundamental principles
about the brain and nervous system, the most complex living structure known in the universe.
2 Figure references to Purves et al., Neuroscience, 5th Ed., Sinauer Assoc., Inc., 2012. [click here]

1
 Cranial and Spinal Nerves

for governing cardiac muscle, smooth muscle or glands. By the conclusion of this and the next tutorial,
you will learn how to locate:
1. nuclei that are the destination of all primary somatic
sensory, visceral sensory, and special sensory input
into the CNS (i.e., the location of all of the
second-order neuronal cell bodies that receive the
primary sensory input), except for olfaction and
vision. The olfactory nerve and the optic nerve are not
included in this discussion; for several reasons they
are atypical.
2. nuclei that are the origin of all of the somatic and
visceral motor output of the CNS (i.e., the location of
all of the alpha motor neurons and preganglionic
visceral motor neurons).

Fig. 1. Both the spinal cord and brainstem receive input

from primary sensory neurons; the cell bodies of these
neurons lie in sensory ganglia. In addition, both the spinal
cord and brainstem give rise to motor output to striated
muscles and to the autonomic ganglia (ANS, autonomic
nervous system; synonymous with visceral motor system).
(Illustration by N.B. Cant)

From the viewpoint of clinical practice, the most important general principle of organization in the
central nervous system is that each CNS function (e.g., perception of sensory stimuli, control of motor
behavior) involves groups of neurons—interconnected through synapses—that are spatially
distributed throughout several CNS subdivisions. Groups of neurons that together subserve a particular
function are called a ‘system’; for example, there are the visual, motor, and somatic sensory systems.
The structures containing the neurons and axons of a particular system are collectively referred to as a
‘pathway’. (The term ‘system’ has a functional connotation, whereas the term ‘pathway’ refers to the
structures involved.) We will study several important sensory and motor pathways in detail in future
tutorials.

Simple tests of cranial nerve function provide clues for localization of

neurological injury and disease
One means for reinforcing your understanding of the functional significance of the cranial nerves is to
actually test their functions in yourself and a willing friend or family member. Review Table A2 below
(from Purves et al., Neuroscience, 5th Ed., Sinauer Assoc., Inc.), which lists the cranial nerve nuclei from
which the sensory and motor components of each nerve arise. Then, consider the means by which you
would assess the functional integrity of the cranial nerves. Actually, there are a number of tests of
cranial nerve function that can be done with very simple materials. These tests provide considerable
information about the presence or absence of normal function in the brainstem and the nerves

2
 Cranial and Spinal Nerves

themselves. Some of these are described on these next few pages to give you an idea of the types of
tests that can be used and why a foundational understanding of functional neuroanatomy is critical for
clinical practice3.

pons

geniculate ganglion

otic ganglion; glossopharyngeal ganglia

X
nucleus ambiguus

Cranial nerves III, IV, and VI

These nerves are tested as a unit, since all supply muscles for eye movement. The oculomotor nerve also
supplies the levator muscle that elevates the lids and the smooth muscles that constrict the pupils.
Range of ocular movement is checked by asking the patient to follow the movements of the examiner’s
fingers as they are moved in all directions of gaze. With involvement of the oculomotor nerve, the
patient will not be able to look up, down or medially with the affected eye. There will also be dilatation
of the pupil and droopiness (ptosis) or closure of the lid on the affected side. If the trochlear nerve is
affected, the patient will be unable to look downward when the eye is adducted. If the abducens nerve
is affected, the patient will not be able to look laterally with the involved eye. In any of these cases, the
patient may complain of double vision. (It is important to remember that either the nerves themselves
or their nuclei in the midbrain and pons may be involved.) Examination of the pupillary reflexes involving
nerves II and III will be explored in a later course session.

Cranial nerve V
The examiner first checks for the presence of the several types of sensation and then determines
whether both sides of the face are equally sensitive. Failure to feel wisps of cotton touching the
forehead, cheeks and jaw indicates anesthesia to light touch. Differences in response on the two sides of
the face indicate increased or decreased sensitivity to light touch. The same procedure is followed in
3
For more on cranial nerve exams, visit neuroexam.com [click here] and explore videos that show tests of cranial nerve
function, with accompanying explanation by Dr. Hal Blumfeld, MD, PhD (author of Neuroanatomy through Clinical Cases;
Sinauer Assoc., Inc.).

3
 Cranial and Spinal Nerves

testing for degree of sensitivity to pinpricks and to warm and cold objects.
The masseter and temporalis muscles (muscles of mastication innervated by the motor component of
the fifth nerve) are examined by palpating them when the jaws are clamped tightly together. The
examiner should note whether there is deviation of the jaw when the mouth is opened.

Cranial nerve VII

The patient is asked to imitate the examiner as he or she looks at the ceiling, wrinkles the forehead,
frowns, smiles, shows teeth, and raises the eyebrows. Any asymmetry of the face is noted. To test the
strength of the eyelid muscles, the patient is asked to keep his or her eyes closed while the examiner
attempts to open them. The sensory portion of the facial nerve can be tested by having the patient
identify the taste of sugar or salt placed on the anterior part of the tongue on each side.

Cranial nerve VIII

The eighth nerve is divided into two parts, the cochlear or auditory nerve and the vestibular nerve.
Special equipment is required to examine the vestibular nerve and it is not tested routinely. (If the
patient gives a history of vertigo or disturbed balance, the possibility of vestibular dysfunction should be
considered and the patient can be given a caloric test, which is described in Purves et al., Neuroscience
5th Ed., Chapter 14, Box 14C.) Preliminary tests of hearing can be done with a tuning fork, but detailed
auditory testing is done by an audiologist.

Cranial nerves IX and X

The pharyngeal gag reflex is tested by touching each side of the pharynx with a tongue depressor or
applicator stick. The palatal reflex is tested by stroking each side of the mucous membrane of the uvula.
The side touched should rise. Normal function of the vagus nerve is revealed by the patient’s ability to
swallow and to speak clearly without hoarseness, by symmetrical movements of the vocal cords, and by
symmetrical movements of the soft palate when he or she says “Ahhh.”

Cranial nerve XI
The examiner 1) palpates and notes the strength of the trapezius muscle while the shoulders are
shrugged against resistance, and 2) palpates and tests the sternocleidomastoid muscle for strength.

Cranial nerve XII

Any lateral deviation of the tongue when it is protruded is noted. The examiner also looks for atrophy or
tremor of the tongue. The strength of the tongue is tested by asking the patient to protrude it and to
move it from side to side against a tongue depressor.

The spinal cord

The spinal cord extends caudally from the brainstem, running from the medullary-spinal junction at
about the level of the first cervical vertebra to about the level of the twelfth thoracic vertebra. The
vertebral column (and the spinal cord within it) is divided into cervical, thoracic, lumbar, sacral, and
coccygeal regions. The peripheral nerves (called the spinal or segmental nerves) that innervate much of
the body arise from the spinal cord’s 31 pairs of spinal nerves. On each side of the midline, the cervical
region of the cord gives rise to eight cervical nerves (C1–C8), the thoracic region to twelve thoracic
nerves (T1–T12), the lumbar region to five lumbar nerves (L1–L5), the sacral region to five sacral nerves

4
 Cranial and Spinal Nerves

(S1–S5), and the coccygeal region to one coccygeal nerve. The segmental spinal nerves leave the
vertebral column through the intervertebral foramina that lie adjacent to the respectively numbered
vertebral body. Sensory information carried by the afferent axons of the spinal nerves enters the cord
via the dorsal roots, and motor commands carried by the efferent axons leave the cord via the ventral
roots. Once the dorsal and ventral roots join, sensory and motor axons (with some exceptions) travel
together in the segmental spinal nerves.
Two regions of the spinal cord are enlarged to accommodate the greater number of nerve cells and
connections needed to process information related to the upper and lower limbs. The spinal cord
expansion that corresponds to the arms is called the cervical enlargement and includes spinal segments
C3–T1; the expansion that corresponds to the legs is called the lumbar enlargement and includes spinal
segments L1–S2. Because the spinal cord is considerably shorter than the vertebral column, lumbar and
sacral nerves run for some distance in the vertebral canal before emerging, thus forming a collection of
nerve roots known as the cauda equina. This region is the target for an important clinical procedure
called a “lumbar puncture” that allows for the collection of cerebrospinal fluid by placing a needle into
the space surrounding these nerves to withdraw fluid for analysis. In addition, local anesthetics can be
safely introduced to produce spinal anesthesia; at this level, the risk of damage to the spinal cord from a
poorly placed needle is minimized.

STUDY QUESTION
Q1. Identify the CORRECT pairing of cranial nerve to function.
A. hypoglossal nerve / movement of facial muscles for expression
B. trigeminal nerve / somatic sensation from face
C. optic nerve / eye movements
D. abducens nerve / medial eye movement (eye adduction)
E. spinal accessory nerve / vocal articulation

Q2. Which of the following structures associated with the spinal cord contains the cell bodies of
primary somatic sensory neurons?
A. dorsal column
B. ventral horn
C. dorsal horn
D. dorsal root ganglia
E. sympathetic chain ganglia

5
 Internal Anatomy of the Brainstem

Medical Neuroscience | Tutorial Notes

Internal Anatomy of the Brainstem

MAP TO NEUROSCIENCE CORE CONCEPTS1

NCC1. The brain is the body's most complex organ.

LEARNING OBJECTIVES
After study of the assigned learning materials, the student will:
1. Identify the major subdivisions of the brainstem and spinal cord, as seen in representative
transverse cross-sections.

NARRATIVE
by Leonard E. White and Nell B. Cant
Duke Institute for Brain Sciences
Department of Neurobiology
Duke University School of Medicine

Introduction
Of chief importance in understanding the organization of the brainstem is knowledge of what is localized
in each embryological subdivision and in any transverse section. This is a significant challenge for every
student of neuroanatomy and we will now turn our attention progressively to this challenge. You have
already faced the first step toward competency with the essential knowledge: recognition of the
external features of each brainstem subdivision, including the associated cranial nerves. After working
through this tutorial, you should be able to recognize any transverse section through the brainstem in
terms of what level is represented and what distinctive features may be present. But before proceeding,
it will be worth again reminding yourself of the basic layout of sensory and motor neurons in the
brainstem and spinal cord.
The central nervous system interacts with the outside world through primary sensory neurons, which
convey information from the body or its environment into the brain and spinal cord, and motor neurons,
which activate striated muscles and modulate the activity of cardiac and smooth muscles and glands
(see Fig. 1 below and/or Figure A1A2). The cell bodies of primary sensory neurons lie in the dorsal root
ganglia or the cranial nerve ganglia. Each neuron gives rise to a peripheral process, which receives
information either directly or through association with receptors, and a central process, which enters
the central nervous system and forms synapses with second order neurons. The cell bodies of somatic
motor neurons lie in clusters or nuclei within the central nervous system and give rise to axons that

1
Visit BrainFacts.org for Neuroscience Core Concepts (©2012 Society for Neuroscience ) that offer fundamental principles
about the brain and nervous system, the most complex living structure known in the universe.
2 Figure references to Purves et al., Neuroscience, 5th Ed., Sinauer Assoc., Inc., 2012. [click here]

1
 Internal Anatomy of the Brainstem

innervate striated muscles in the body or head. In this tutorial, you will be especially concerned with the
organization of these second-order sensory neurons and somatic motor neurons. You will also be
introduced to other motor neurons that are part of the visceral motor system (a.k.a., autonomic nervous
system) and are indirectly responsible for governing cardiac muscle, smooth muscle or glands. By the
conclusion of this learning experience, you will learn how to locate:
1. nuclei that are the destination of all primary somatic
sensory, visceral sensory, and special sensory input
into the CNS (i.e., the location of all of the
second-order neuronal cell bodies that receive the
primary sensory input), except for olfaction and
vision. The olfactory nerve and the optic nerve are not
included in this discussion; for several reasons they
are atypical.
2. nuclei that are the origin of all of the somatic and
visceral motor output of the CNS (i.e., the location of
all of the alpha motor neurons and preganglionic
visceral motor neurons).

Fig. 1. Both the spinal cord and brainstem receive input

from primary sensory neurons; the cell bodies of these
neurons lie in sensory ganglia. In addition, both the spinal
cord and brainstem give rise to motor output to striated
muscles and to the autonomic ganglia (ANS, autonomic
nervous system; synonymous with visceral motor system).
(Illustration by N.B. Cant)

From the viewpoint of clinical practice, the most important general principle of organization in the
central nervous system is that each CNS function (e.g., perception of sensory stimuli, control of motor
behavior) involves groups of neurons—interconnected through synapses—that are spatially
distributed throughout several CNS subdivisions. Groups of neurons that together subserve a particular
function are called a ‘system’; for example, there are the visual, motor, and somatic sensory systems.
The structures containing the neurons and axons of a particular system are collectively referred to as a
‘pathway’. (The term ‘system’ has a functional connotation, whereas the term ‘pathway’ refers to the
structures involved.) We will study several important sensory and motor pathways in detail in future
tutorials.
If damage to the CNS at every level gave rise to exactly the same signs and symptoms, it would not be
worthwhile for you to learn the details of neuroanatomy. However, as neurologists and neuroscientists
recognized long ago, the neurons involved in specific functions occupy specific locations in the central
nervous system. Even those systems that are represented in multiple subdivisions bear different
physical relationships to one another from one subdivision to the next. Because neurons that subserve
specific functions occupy specific locations, the combinations of neurological signs and symptoms
exhibited by particular patients often provide detailed information about the location of damage in the
CNS. These principals will guide our survey of the cranial nerve nuclei that are distributed across the

2
 Internal Anatomy of the Brainstem

three major subdivisions of the brainstem. Knowledge of their location and function will provide key
information that will help you localize neurological injury and dysfunction in clinical patients.

The internal anatomy of the brainstem

The internal organization of the brainstem is considerably more complicated than that of the spinal
cord. However, two factors work in your favor as you study its features. First, important general
principles of organization of the spinal cord also hold true for the brainstem. Second, much of the
complexity of the brainstem is contributed by cell groups and axon tracts that will not be considered in
this course. In the following discussion, the general plan of organization of the brainstem is presented
first. Then, the prominent internal features that characterize each subdivision are identified.
It would be convenient if each subdivision of the brainstem were sufficiently homogeneous along its
length that one cross-section could serve as a ‘typical’ representative for the entire subdivision.
However, the brainstem changes continuously along its length—the subdivision into three parts is
somewhat arbitrary. As a compromise between examining three sections (one for each subdivision) and
hundreds, seven sections of the brainstem are shown to serve as representatives (Figure 2).
Once you understand the organization
of these seven levels and the way
various pathways traverse them, you
should be able to identify the location
of any section through the brainstem
and the important pathways
represented in it.

Figure 2. Drawing of the dorsal surface

of the brainstem with lines to indicate
the seven levels that will be illustrated in
the following pages. These same
sections are also annotated in the
Brainstem Cross Sectional Atlas in
Sylvius4 Online. (Illustration courtesy of
Pyramis Studios, Durham NC)

A schematic overview of the levels of

the brainstem to be discussed is
presented in Figure 3. At this stage, it is not important to study the details; we will come back to them.
For now, three points should be taken from the figure. (1) All of the sections are shown at the same
magnification. In most atlases (including Sylvius4 Online), the smaller sections are magnified more than
the larger ones, and it is easy to lose sight of the relative proportions of the different subdivisions. (2)
The cranial nerve nuclei lie in the tegmentum of the brainstem, as do many of the major ascending and
descending tracts. (3) Just as in the spinal cord, the nuclei that receive sensory inputs via the cranial
nerves are spatially separate from those that give rise to motor output. The sensory nuclei are located
laterally in the brainstem, whereas the motor nuclei are located medially. The spatial segregation of
sensory and motor functions provides an important clue for localization of focal damage in the
brainstem.

3
 Internal Anatomy of the Brainstem

4
 Internal Anatomy of the Brainstem

Figure 3. (previous page) A. Sagittal view of the brainstem to show the level of the sections in part B. (The
small curved arrow indicates the location of the median aperture through which cerebrospinal fluid escapes
from the ventricular system.) B. Sections through the brainstem. (These are not drawings of the sections
illustrated in the following figures, but they are taken from approximately the same levels, with an additional
section to illustrate midbrain structures.) The sections are all drawn at the same magnification (a little less than
two times actual size). The tegmentum of the brainstem is indicated in gray. Note that although the sections
themselves vary greatly in size, the tegmentum is approximately the same size in all of them. Much of the
effort in this course will be spent on learning the organization of the structures in the tegmentum. The
positions of the cranial nerve nuclei (and also the sensory nuclei known as the dorsal column nuclei, which will
be covered in a later session of this course) are indicated. Motor nuclei are represented in red and yellow,
indicating somatic motor and visceral motor nuclei, respectively; sensory nuclei are represented in blue;
important tracts are represented in unfilled outline. Note that the tracts are external to the sensory and motor
nuclei, as is the case in the spinal cord. (Only a portion of the cerebellum is included in the drawings of sections
4, 5 and 6). (Illustration by N.B. Cant)

In Figures 4–9 on the following pages, major landmarks in each of the subdivisions are identified in
sections prepared to enhance the appearance of myelin (again, it is conventional to prepare sections of
the brainstem and spinal cord with stains that make the white matter appear dark). As usual, be sure to
focus on the structures identified in the figure legends in bold font.

Medulla oblongata
[next page]

5
 Internal Anatomy of the Brainstem

Dorsal column nuclei (leaders on left Dorsal columns

side of image) and dorsal columns
(leaders on right side) Lateral
column

Dorsal Dorsal
horn? Dorsal columns
horn?

Dorsal
horn?

Medullary pyramids

Pyramidal
Medullary pyramid decussation

Figure 4. Section through the caudal medulla (left picture; “11-medulla” in Sylvius4 Online). The shape is similar
to that of the spinal cord (a section through the cervical cord is shown in top right picture; “14-Spinal
Cord-cervical” in Sylvius4). But, although the internal organization bears a resemblance to that of the spinal
cord, there are some obvious differences. First, the medullary pyramids occupy the base of the caudal medulla;
the anterior columns of the spinal cord do not contain so many fibers (and do not have the same pyramidal
shape). On the other hand, the lateral columns are quite large in the cervical spinal cord, but there are
relatively few myelinated axons in the lateral part of the caudal medulla. The bottom right picture is a
photograph of the point of transition between the spinal cord and medulla (“13-medulla” in Sylvius4 Online).
Here, at the level of the pyramidal decussation, the axons in the pyramids not only cross the midline, they also
move laterally to enter the lateral columns of the spinal cord. This change in relative location of the axons
explains why the anterior columns of the spinal cord are smaller in size and why the lateral columns are larger
when the spinal cord is compared to the caudal medulla. A second difference between the spinal cord and
lower medulla is that in the spinal cord, the dorsal columns are made up exclusively of white matter. In the
caudal medulla, you can still see bundles of axons dorsally but now cell groups (the dorsal column nuclei) have
appeared in the same location. These nuclei are second order sensory nuclei that will be discussed in a later
session of this course. Finally, note that a cell group that resembles the dorsal horn is also present in the caudal
medulla (it is labeled “dorsal horn?”). This is a nucleus known as the spinal trigeminal nucleus, and it is
continuous with the dorsal horn of the spinal cord and serves comparable functions, except for representation
of a different region of the body.

6
 Internal Anatomy of the Brainstem

Inferior cerebellar
peduncle

Inferior olivary
nucleus

Medullary pyramids

Figure 5. The rostral medulla is easy to identify and is not likely to be confused with any other part of the brain
(section shown is “9-medulla” in Sylvius4 Online). It features the large nuclei known as the paired inferior
olivary nucleus (this is what accounts for the outward bulging seen superficially as the inferior olive). This
nucleus is part of an extensive group of brainstem nuclei that project to the cerebellum. Together with the
medullary pyramids, they form the base of the rostral medulla. A prominent fiber bundle on the lateral surface
of the medulla is the incipient inferior cerebellar peduncle (not yet attached to the cerebellum at this point).
The thin roof of the fourth ventricle (IV) has been torn off of this specimen. It is made up of pia, ependyma, and
blood vessels. You can see that the tegmentum of the medulla contains many different cell groups. They will
be discussed later.

With reference to Figures 4 & 5 and the chart below, carefully inspect the internal features of the
medulla from its caudal union with the spinal cord to the pons. Spend some time browsing these
medullary sections (and the sections in Sylvius4 Online), and find each of the internal features described
in the chart below.

7
 Internal Anatomy of the Brainstem

Subdivision Surface feature Internal structure

Gracile tract Gracile tract & nucleus
(dorsal surface)  medial, superficial bundle of myelinated axons
 pair of extended longitudinal bulges or columns on arising from the dorsal column of the spinal
either side of a deep midline furrow; technically, cord
this bulge is called the tuberculum gracilis, which is  just deep to the gracile tract is the gracile
formed by the underlying gracile tract nucleus, a compact gray matter structure that
 continuation of the tract of the dorsal spinal cord receives the synapses made by gracile tract
axons
Cuneate tract Cuneate tract & nucleus
(dorsal surface)  just lateral to the gracile tract, superficial
Caudal  pair of extended longitudinal bulges or columns bundle of myelinated axons arising from the
medulla just lateral to the gracile tracts; technically, this dorsal column of the spinal cord
bulge is called the tuberculum cuneatus, which is  at the superior “head” of the cuneate tract is
(Figure 4)
formed by the underlying cuneate tract the cuneate nucleus, a compact gray matter
 continuation of the tract of the dorsal spinal cord structure that receives the synapses made by
cuneate tract axons
Pyramidal decussation Pyramidal decussation
(ventral surface)  see Medullary pyramids below
 see Medullary pyramids below  midline crossing of dense bundles of
 apparent “stitching” of fibers that cross the myelinated axons that run the longitudinal
midline extent of the ventral brainstem
 accounts for the formation of the lateral and
ventral (anterior) corticospinal tracts of the
spinal cord
Medullary pyramids Medullary pyramids
(ventral surface)  dense bundle of myelinated axons that run the
 pair of extended longitudinal bulges or columns on longitudinal extent of the ventral brainstem;
either side of a deep midline furrow these axons are also known as the corticospinal
tract
 these same axons are present in the internal
capsule, cerebral peduncles, basilar pons, and
about 90% are present in the lateral columns
of the spinal cord
Middle to
Inferior olive Inferior olivary nucleus
rostral (ventral-lateral surface)
medulla  prominent nucleus of the ventral-lateral
 pair of elongated bulges just lateral to the medulla just dorsal to the medullary pyramids
(Figure 5)
pyramids; a shallow furrow separates the pyramid  note the highly convoluted bands of gray
and olive on each side matter that account for the superficial,
ventral-lateral bulge
Hypoglossal nerve (XII) Hypoglossal nerve roots & nucleus
(ventral-lateral surface)  nerve roots emerge between the medullary
 exits through ventral-medial surface pyramid and the olive
 trace these nerve roots dorsally to their origin
in the hypoglossal nucleus, located along the
dorsal midline

8
 Internal Anatomy of the Brainstem

Figure 6. (Next page). The caudal and middle pons (upper and lower sections, respectively; “7-pons” &
“6-pons” in Sylvius4 Online) look very similar at first inspection. We need two levels to represent the pons
because there are different groups of cranial nerve nuclei at the two levels. These sections are attached to the
cerebellum (a dead giveaway that we are in the pons) by the massive middle cerebellar peduncles (cut on the
lateral edge of the sections). The base of the pons is made up of a mix of cells—the pontine gray matter and
transversely coursing fibers—fibers that arise from the cells in the pontine gray matter and travel into the
cerebellum via the middle cerebellar peduncle. Not all the fibers in the base of the pons are running
transversely. Note that some appear to be traveling perpendicular to the plane of section. These will emerge
on the base of the medulla as the medullary pyramids. The tegmentum of the pons looks similar at both levels,
but the nuclei contained at each level are different.

Pons
With reference to Figures 6 & 7 and the chart below, carefully inspect the internal features of the pons.
Spend some time browsing these pontine sections (and the sections in Sylvius4 Online), and find each of
the internal features described in the chart below.

9
 Internal Anatomy of the Brainstem

Superior
cerebellar
peduncle

Inferior
Fourth cerebellar
ventricle peduncle

Middle
cerebellar
peduncle

Pontine gray
axons that will form
matter
medullary pyramids
Superior
cerebellar
peduncle

Fourth
ventricle

Middle
cerebellar
peduncle

axons that will form Pontine gray

medullary pyramids matter

10
 Internal Anatomy of the Brainstem

Cerebral
aqueduct

Superior
cerebellar
peduncle

Pontine gray
matter

axons passing through

cerebral peduncle into pons

Figure 7. At the junction of the pons and midbrain, the brainstem looks relatively simple. The massive pontine
base is about to give way to the cerebral peduncles. Dorsal to the base, the brainstem is reduced to the
tegmentum. The fourth ventricle, which you saw in the sections through the pons, is disappearing to be
replaced by the cerebral aqueduct. (Section is “4-pons” in Sylvius4 Onilne)

11
 Internal Anatomy of the Brainstem

Subdivision Surface feature Internal structure

Middle cerebellar peduncle Pontocerebellar fibers & middle cerebellar peduncle
(ventral-lateral surface)  the ventral half of the pons (also called the basilar pons)
 massive system of transverse fibers contains gray matter, longitudinal axons, and transverse
that “bridge” the longitudinal axis of fibers called the pontocerebellar fibers that decussate and
the brainstem; these fibers originate in form the contralateral middle cerebellar peduncle
the basal region of the pons and  these fibers arise from a scattering of gray matter in the
continue around its ventral-lateral basilar pons, called the pontine nuclei, and terminate in
aspect to enter the cerebellum the contralateral cerebellum
 also in the basilar pons are prominent fascicles of axons
Middle of from the cerebral cortex that project to various nuclei of
pons the brainstem and the spinal cord; collectively, these axons
(Figure 6, are the corticobulbar/corticospinal fibers
lower) Trigeminal nerve (V) Trigeminal nerve roots & nucleus
(ventral-lateral surface)  trace the nerve V roots dorsally to their origin in the
 enters/exits pons by penetrating the trigeminal nuclear complex; at this level, note the location
transverse, pontocerebellar fibers of the trigeminal motor nucleus and, just lateral to it, the
principal (chief sensory) nucleus
 now, keep your eye in this same general region and
section caudally: in this same dorsal-lateral position in the
caudal pons and throughout the medulla, the spinal
trigeminal nucleus and the spinal trigeminal tract are
present (the spinal nucleus can be further subdivided)
Abducens nerve (VI) Abducens nerve roots & nucleus
(ventral-medial surface)  explore the medial tegmentum of the pons and locate
 enters/exits near the midline at the nerve VI roots; note how they course through the basilar
pontomedullary junction (most medial pons just lateral to the corticobulbar/corticospinal fibers
of the three that emerge from this  trace these nerve roots dorsally to their origin in the
junction) abducens nucleus, which is located along the dorsal
midline
Facial nerve (VII) Facial nerve roots & nucleus
(ventral-lateral surface)  explore the lateral tegmentum of the pons and locate
 enters/exits through ventral-lateral nerve VII roots; note how they trace a most unusual
surface at pontomedullary junction trajectory around the dorsal aspect of the abducens
(middle of the three that emerge from nucleus (cf. Figure 5.14)
this junction, just medial to CN VIII)  it may not be possible to trace these nerve roots all the
way back to their origin in the facial nucleus, which is
Caudal pons located just medial and ventral to the trigeminal nuclear
(Figure 6, complex
upper)  nerve VII roots exit the facial nucleus medially, then course
dorsally around the abducens nucleus, and finally
ventral-laterally toward a lateral exit (this is how CN VII
ends up being lateral to CN VI)
Vestibulocochlear nerve (VIII) Vestibular nuclear complex
(ventral-lateral surface)  explore the lateral tegmentum of the pons and locate
 enters through ventral-lateral surface nuclei of the vestibular nuclear complex; you will find the
at pontomedullary junction (most vestibular nuclei dorsal to the trigeminal nuclear complex
lateral of the three that emerge from and spinal trigeminal tract
this junction, just lateral to CN VII)  So what about the cochlear division of CN VIII? It
terminates in a superficial nucleus of the dorsal-lateral
upper medulla called the cochlear nucleus. Although not
labeled in Sylvius4, it is visible in the section labeled
“8-Medulla” as the gray matter that wraps around the
dorsal-lateral surface of the inferior cerebellar peduncle

12
 Internal Anatomy of the Brainstem

Midbrain
With reference to Figures 8 & 9 and the chart below, carefully inspect the internal features of the
midbrain. Spend some time browsing these pontine sections (and the sections in Sylvius4 Online), and
find each of the internal features described in the chart below.

Superior
colliculus
Medial geniculate
nucleus (part of Cerebral
aqueduct
Lateral geniculate the thalamus)
nucleus (part of
the thalamus)

Cerebral peduncle

Substantia nigra Red nucleus

Figure 8. This section is through the rostral midbrain and so it cuts through the superior colliculus. The space
between the colliculi is the cerebral aqueduct. The cerebral peduncles form the base of the midbrain. Two very
large nuclei lie dorsal to them. These are the substantia nigra and the red nucleus; they are discussed in a later
session. (A small part of the dorsal thalamus, including the medial and lateral geniculate nuclei, are also
included in this section.) (Section is “2-midbrain” in Sylvius4 Online)

13
 Internal Anatomy of the Brainstem

Third
Thalamus ventricle

Subthalamic
nucleus
Cerebral peduncle

Red nucleus
Mammillary bodies
(part of the hypothalamus)

Figure 9. The last section in the series through the brainstem is cut through the junction of the midbrain and
diencephalon. Structures of the midbrain are seen medially, but laterally the diencephalon has appeared. The
cerebral peduncles will become continuous with the internal capsule a little rostral to this level. Likewise, the
cerebral aqueduct will become continuous with the third ventricle. Note the presence of the subthalamic
nucleus on the dorsal aspect of the cerebral peduncle (in the place where the substantia nigra is located a
centimeter inferior to this level; cf. Figure 8). (Section is “1-midbrain-diencephalon junction” in Sylvius4 Online)

14
 Internal Anatomy of the Brainstem

Subdivision Surface feature Internal structure

Cerebral peduncles Cerebral peduncles
(ventral surface)  technically, “cerebral peduncle” refers to the entire ventral midbrain,
 large, longitudinal “stalks” including the midbrain tegmentum and the fiber systems that run through
the stalks; however, it is common to use the term “cerebral peduncle” to
(peduncle means stalk) that
refer specifically to these fiber systems (the proper term for these ventral
occupy the ventral midbrain
portions of the peduncles—where the fibers are—is pes or basis
pedunculi)
 the cerebral peduncles comprise efferent fibers of the cerebral cortex
that terminate in the brainstem and spinal cord; these fibers are referred
to collectively as the corticobulbar/corticospinal fibers; this compound
terms indicates that the some of these fibers terminate among brainstem
nuclei (“bulbar” refers to the brainstem and cranial nerve nuclei), while
other fibers continue and terminate in the spinal cord
Midbrain  it is important to recognize the course of these fibers from their origin in
(Figure 8) the cerebral cortex through brainstem: cerebral cortex → subcortical
white matter → internal capsule → cerebral peduncle → basilar pons →
medullary pyramids → lateral and anterior (ventral) corticospinal tract
 there are about 20 million axons in each cerebral peduncle; can you guess
how many axons are present in medullary pyramid by simply noting the
difference in size of these two structures?3 (the majority of these axons
never reach the spinal cord)
 now consider the tegmentum of the midbrain; just dorsal to the cerebral
peduncles (pes pedunculi) there is an important gray matter nucleus
called the substantia nigra, and in a similar position but just a bit more
rostral is the subthalamic nucleus; you will learn much more about these
nuclei when we study the basal ganglia
 just dorsal to the substantia nigra, is a spherical gray matter structure
called the red nucleus, which modulates cerebellar function
Oculomotor nerve (III) Oculomotor nerve roots & nuclear complex
(ventral surface)  trace these nerve roots dorsally to their origin in the nuclei of the
 exits through ventral surface oculomotor complex along the midline of the dorsal tegmentum; here
you will find two divisions: the oculomotor nucleus and the
just medial to cerebral
Edinger-Westphal nucleus
peduncles (in the
 this nuclear complex is embedded within gray matter that surrounds the
interpeduncular fossa)
cerebral aqueduct, termed the periaqueductal (or central) gray

Inferior colliculi Inferior colliculi

(dorsal surface)  in the caudal midbrain, the inferior colliculi are gray matter structures
 inferior pair of the four that occupy a position just dorsal and lateral to the periaqueductal gray
(see section “3 - Midbrain”)
bumps that are visible in
 together with the superior colliculi, they form the “roof” of the midbrain
brainstem
(above the cerebral aqueduct); for this reason, these four bumps are also
model/illustration, but are
called the tectum (tectum means roof)
normally covered by the
 the trochlear nerve exits the dorsal surface of the brainstem just caudal
cerebellum to the inferior colliculus (see Brainstem Model in Surface Anatomy
module)
 although that nerve is not visible in section 3 – Midbrain, you can see the
small trochlear nuclei where you should expect to find somatic motor
nuclei, along the midline of the dorsal tegmentum
Superior colliculi Superior colliculi
(dorsal surface)  in the rostral midbrain, the superior colliculi are laminated gray matter
 superior pair of the four structures that occupy a position just dorsal and lateral to the
periaqueductal gray matter (see section lableled “2 - Midbrain”)
bumps that are visible in
brainstem model/illustration  together with the inferior colliculi, they form the “roof” (tectum) of the
midbrain (above the cerebral aqueduct)

3
There are about one million axons in each medullary pyramid.

15
 Internal Anatomy of the Brainstem

STUDY QUESTIONS
Q1. What is the brainstem nucleus that accounts for the outward bulge just lateral to the nerve
roots of CN XII (hypoglossal nerve)?
A. gracile nucleus
B. cuneate nucleus
C. inferior olivary nucleus
D. facial motor nucleus
E. spinal trigeminal nucleus

Q2. Which of the following is a defining feature of the pons?

A. cedullary pyramids
B. cerebral peduncles
C. inferior olivary nucleus
D. pontocerebellar fibers forming the middle cerebellar peduncle
E. dorsal column nuclei

Q3. Which of the following cranial nerve nuclei is found in the midbrain?
A. abducens nucleus
B. hypoglossal nucleus
C. oculomotor nucleus
D. facial motor nucleus
E. red nucleus

16
 Cranial  Nerve  Nuclei  

Medical  Neuroscience  |  Tutorial  Notes  

Cranial  Nerve  Nuclei  

MAP  TO  NEUROSCIENCE  CORE  CONCEPTS1  

NCC1.   The  brain  is  the  body's  most  complex  organ.  

LEARNING  OBJECTIVES  
After  study  of  the  assigned  learning  materials,  the  student  will:  
1. Identify  the  major  subdivisions  of  the  brainstem  and  spinal  cord,  as  seen  in  representative  
transverse  cross-­‐sections.  
2. Discuss  the  relationship  between  the  cranial  nerves  and  the  corresponding  cranial  nerve  nuclei.  

NARRATIVE  
by  Leonard  E.  White  and  Nell  B.  Cant  
Duke  Institute  for  Brain  Sciences  
Department  of  Neurobiology  
Duke  University  School  of  Medicine  

Introduction  
Of  chief  importance  in  understanding  the  organization  of  the  brainstem  is  knowledge  of  what  is  localized  
in  each  embryological  subdivision  and  in  any  transverse  section.  This  is  a  significant  challenge  for  every  
student  of  neuroanatomy  and  we  will  now  turn  our  attention  progressively  to  this  challenge.  You  have  
already   faced   the   first   step   toward   competency   with   the   essential   knowledge:   recognition   of   the  
external  features  of  each  brainstem  subdivision,  including  the  associated  cranial  nerves.  After  working  
through   this   tutorial,   you   should   be   able   to   recognize   how   the   cranial   nerves   relate   to   gray   matter  
structures   in   the   brainstem   that   grew   out   the   axons   in   the   cranial   nerves   (motor   axons)   or   receive  
synaptic  input  from  ganglionic  neurons  associated  with  the  nerves  (sensory  axons).  Before  proceeding,  it  
will   be   worth   reminding   yourself   of   the   basic   layout   of   sensory   and   motor   neurons   in   the   brainstem   and  
spinal  cord.  
The   central   nervous   system   interacts   with   the   outside   world   through   primary   sensory   neurons,   which  
convey  information  from  the  body  or  its  environment  into  the  brain  and  spinal  cord,  and  motor  neurons,  
which   activate   striated   muscles   and   modulate   the   activity   of   cardiac   and   smooth   muscles   and   glands  
(see  Fig.   1  below  and/or  Figure   A1A2).  The  cell  bodies  of  primary  sensory  neurons  lie  in  the  dorsal  root  
ganglia   or   the   cranial   nerve   ganglia.   Each   neuron   gives   rise   to   a   peripheral   process,   which   receives  
information   either   directly   or   through   association   with   receptors,   and   a   central   process,   which   enters  

1
  Visit  BrainFacts.org  for  Neuroscience  Core  Concepts  (©2012  Society  for  Neuroscience  )  that  offer  fundamental  principles  
about  the  brain  and  nervous  system,  the  most  complex  living  structure  known  in  the  universe.  
2 Figure  references  to  Purves  et  al.,  Neuroscience,  5th  Ed.,  Sinauer  Assoc.,  Inc.,  2012.  [click  here]

1  
 Cranial  Nerve  Nuclei  

the  central  nervous  system  and  forms  synapses  with  second  order  neurons.  The  cell  bodies  of  somatic  
motor   neurons   lie   in   clusters   or   nuclei   within   the   central   nervous   system   and   give   rise   to   axons   that  
innervate  striated  muscles  in  the  body  or  head.  In  this  tutorial,  you  will  be  especially  concerned  with  the  
organization   of   these   second-­‐order   sensory   neurons   and   somatic   motor   neurons.   You   will   also   be  
introduced  to  other  motor  neurons  that  are  part  of  the  visceral  motor  system  (a.k.a.,  autonomic  nervous  
system)   and   are   indirectly   responsible   for   governing   cardiac   muscle,   smooth   muscle   or   glands.   By   the  
conclusion  of  this  learning  experience,  you  will  learn  how  to  locate:  
1. nuclei   that   are   the   destination   of   all   primary   somatic  
sensory,   visceral   sensory,   and   special   sensory   input  
into   the   CNS   (i.e.,   the   location   of   all   of   the  
second-­‐order   neuronal   cell   bodies   that   receive   the  
primary   sensory   input),   except   for   olfaction   and  
vision.  The  olfactory  nerve  and  the  optic  nerve  are  not  
included   in   this   discussion;   for   several   reasons   they  
are  atypical.  
2. nuclei   that   are   the   origin   of   all   of   the   somatic   and  
visceral  motor  output  of  the  CNS  (i.e.,  the  location  of  
all   of   the   alpha   motor   neurons   and   preganglionic  
visceral  motor  neurons).  
 
 
Fig.   1.   Both   the   spinal   cord   and   brainstem   receive   input  
from   primary   sensory   neurons;   the   cell   bodies   of   these  
neurons   lie   in   sensory   ganglia.   In   addition,   both   the   spinal  
cord   and   brainstem   give   rise   to   motor   output   to   striated  
muscles   and   to   the   autonomic   ganglia   (ANS,   autonomic  
nervous   system;   synonymous   with   visceral   motor   system).  
(Illustration  by  N.B.  Cant)  
 

From   the   viewpoint   of   clinical   practice,   the   most   important   general   principle   of   organization   in   the  
central  nervous  system  is  that  each  CNS   function  (e.g.,  perception  of  sensory  stimuli,  control  of  motor  
behavior)   involves   groups   of   neurons—interconnected   through   synapses—that   are   spatially  
distributed  throughout  several  CNS  subdivisions.  Groups  of  neurons  that  together  subserve  a  particular  
function   are   called   a   ‘system’;   for   example,   there   are   the   visual,   motor,   and  somatic   sensory   systems.  
The  structures  containing  the  neurons  and  axons  of  a  particular  system  are  collectively  referred  to  as  a  
‘pathway’.   (The   term   ‘system’   has   a   functional   connotation,   whereas   the   term   ‘pathway’   refers   to   the  
structures   involved.)   We   will   study   several   important   sensory   and   motor   pathways   in   detail   in   future  
tutorials.  
If  damage  to  the  CNS  at  every  level  gave  rise  to  exactly  the  same  signs  and  symptoms,  it  would  not  be  
worthwhile  for  you  to  learn  the  details  of  neuroanatomy.  However,  as  neurologists  and  neuroscientists  
recognized  long  ago,  the  neurons  involved  in  specific  functions  occupy  specific  locations  in  the  central  
nervous   system.   Even   those   systems   that   are   represented   in   multiple   subdivisions   bear   different  
physical  relationships  to  one  another  from  one  subdivision  to  the  next.  Because  neurons  that  subserve  
specific   functions   occupy   specific   locations,   the   combinations   of   neurological   signs   and   symptoms  

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exhibited  by  particular  patients  often  provide  detailed  information  about  the  location  of  damage  in  the  
CNS.   These   principals   will   guide   our   survey   of   the   cranial   nerve   nuclei   that   are   distributed   across   the  
three   major   subdivisions   of   the   brainstem.   Knowledge   of   their   location   and   function   will   provide   key  
information  that  will  help  you  localize  neurological  injury  and  dysfunction  in  clinical  patients.

An  embryological  framework  for  understanding  the  cranial  nerve  nuclei  

The   cranial   nerve   nuclei   are   made   up   of   the   neurons   in   the   brainstem   that   receive   primary   sensory  
inputs  or  that  give  rise  to  motor  outputs.  Just  as  there  are  cell  groups  in  the  dorsal  horn  of  the  spinal  
cord  that  receive  sensory  information  and  cell  groups  in  the  ventral  horn  that  contain  motor  neurons,  
there  are  separate  sensory  and  motor  nuclei  in  the  brainstem.  
The  spinal  cord  receives  sensory  information  from  the  body  surface,  muscles  (via  the  muscle  spindles)  
and  the  viscera,  and  sends  motor  axons  to  striated  muscles  and  to  the  autonomic  ganglia.  These  same  
inputs  and  outputs  exist  for  the  head.  In  addition,  there  are  specialized  sensory  inputs  in  the  head  that  
do  not  have  equivalents  in  the  spinal  cord.  These  include  the  inputs  for  hearing,  balance  and  taste.  The  
motor  outputs  are  just  a  little  more  complicated  as  well.  There  are  nuclei  which  innervate  the  extrinsic  
eye   muscles   and   the   tongue.   Since   the   muscles   that   are   innervated   are   derived   from   somites,   these  
motor  neurons  are  exactly  equivalent  to  those  in  the  ventral  horn,  which  also  innervate  muscles  derived  
from  somites.  In  addition,  there  are  nuclei  in  the  brainstem  that  innervate  the  muscles  derived  from  the  
branchiomeres   of   the   embryonic   pharyngeal   arches   (jaw   muscles,   muscles   of   facial   expression,   the  
pharynx   and   larynx).   There   is   only   one   such   cell   group   in   the   spinal   cord;   it   innervates   the   trapezius   and  
sternocleidomastoid   muscles,   which   are   also   derived   from   branchiomeres.   It   is   included   with   the   cranial  
nerve  nuclei,  since  it  gives  rise  to  the  spinal  part  of  cranial  nerve  XI.  Finally,  there  are  cell  groups  in  the  
brainstem  that  form  part  of  the  visceral  motor  (autonomic)  system  and  send  axons  to  autonomic  ganglia  
in  organs  throughout  the  body.  Now,  let’s  appreciate   the   organization   of   these   nuclei   in   each   division   of  
the  brainstem.  
The   organization   of   the   sensory   and   motor   neurons   in   the   spinal   cord   and   brainstem   are   similar,   for  
reasons  that  are  clear  when  one  considers  the  development  of  these  two  regions  of  the  neural  tube—as  
explained   in   Fig.   2   (next   page).   Sensory   neurons,   which   are   located   dorsally   in   the   spinal   cord,   are  
located   laterally   in   the   medulla   and   pons.   Motor   neurons,   which   are   located   ventrally   in   the   spinal   cord,  
are  located  medially  in  the  medulla,  pons,  and  midbrain.  
Ten  sets  of  cranial  nerves  are  associated  with  the  brainstem.  These  nerves  supply  sensory  inputs  to  or  
derive  motor  output  from  16  sets  of  cranial  nerve  nuclei.  In  the  following  discussion,  ways  of  grouping  
these   nuclei   to   make   them   easier   to   remember   are   presented.   Next,   the   way   in   which   they   match   up  
with  the  nerves  will  be  described.  Finally,  they  will  be  located  on  the  cross-­‐sections  of  the  brainstem.  
One   further   point   can   be   made   from   Fig.  2.   In   the   medulla,   the   motor   column   that   gives   rise   to   somatic  
motor  nuclei  also  gives  rise  to  the  motor  neurons  that  will  innervate  the  branchiomeric  muscles.  These  
motor  neurons  migrate  from  the  midline  into  the  ventral-­‐lateral  part  of  the  tegmentum  and  send  their  
axons  out  in  nerves  that  exit  the  brain  laterally  (i.e.,  V,  VII,  IX,  X,  and  XI).  The  somatic  motor  neurons,  on  
the   other   hand,   send   their   axons   out   ventrally   (in   a   line   with   ventral   roots   of   the   spinal   cord),   except   for  
the  trochlear  nucleus,  which  is  the  only  motor  nucleus  to  grow  its  axons  out  of  the  dorsal  aspect  of  the  
CNS.   Oddly,   the   parasympathetic   preganglionic   neurons   (visceral   motor   neurons)   in   the   medulla   and  
pons   also   send   their   axons   out   laterally;   in   the   spinal   cord   (and   in   the   midbrain),   the   autonomic  
preganglionic  axons  leave  in  the  ventral  roots.  All  of  the  sensory  inputs  enter  the  brain  laterally.  
   

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 Cranial  Nerve  Nuclei  

 
Spinal  cord   Medulla  

Fig.   2.  Drawings  of  cross-­‐sections  through  the  embryonic  (top  panels)  and  adult  (bottom  panels)  spinal  cord  
and  medulla.  In  the  embryo,  four  columns  of  dividing  neurons  can  be  identified  which  give  rise  to  somatic  and  
visceral  sensory  and  motor  cell  groups  in  the  adult.  (Indicated  in  different  shades  of  gray.)  Because  the  medulla  
has   a   much   wider   roof   than   the   spinal   cord,   the   cell   columns   that   are   located   dorsally   in   the   spinal   cord   get  
pushed  out  laterally  in  the  medulla.  The  cell  columns  that  are  located  ventrally  in  the  spinal  cord  are  located  
medially  in  the  medulla.  The  same  relation  holds  true  for  the  sensory  and  motor  cell  groups  in  the  adult.  (CC,  
central  canal  of  the  spinal  cord;  IV,  fourth  ventricle)  (Illustration  by  N.B.  Cant)  
 

Location  and  function  of  the  cranial  nerve  nuclei  

The   sixteen   cranial   nerve   nuclei   can   be   most   easily   remembered   if   they   are   assembled   into   functional  
groups   and   anatomical   location   (see   Table   on   the   next   page—   Table   A3   from   Purves   et   al.,  
Neuroscience,   5th   Ed.;   and   Fig.   3).   Three   of   the   groups   are   motor   nuclei:   a   somatic   motor   group,   a  
branchial   motor   group,   and   a   parasympathetic   preganglionic   group   (the   corresponding   sympathetic  
preganglionic  group  is  in  the  thoracic  segments  of  the  spinal  cord).  The  other  three  groups  are  sensory  
nuclei:  general  sensory,  special  sensory,  and  visceral  sensory.  
 

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How   do   these   nuclei   relate   to   the   components   of   the   cranial   nerves   that   you   studied   in   a   previous  
tutorial?  Table  A2  (from  Purves  et  al.,  Neuroscience,  5th  Ed.)  lists  the  cranial  nerve  nuclei  from  which  the  
sensory  and  motor  components  of  each  nerve  arise.  
 

pons  

geniculate  ganglion  

otic  ganglion;  glossopharyngeal  ganglia  

X  
nucleus  ambiguus  

 
 
Taken  together,  these  tables   illustrate  the  point  that  most  of  the  cranial  nerves  are  connected  to  only  
one  or  two  cranial  nerve  nuclei.  Only   three   nerves   carry   components   from   more   than   two   nuclei.   These  
nerves—VII,  IX,  and  X—each  carry  five  components:  a  branchial  motor  component,  a  parasympathetic  

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 Cranial  Nerve  Nuclei  

component,  a  somatic  sensory  component,  a  special  visceral  sensory  component  (taste),  and  a  general  
visceral  sensory  component.  These  three  nerves  lack  a  somatic  motor  component.  

Location  of  the  cranial  nerve  nuclei  in  brainstem  cross-­‐sections  

The   internal   organization   of   the   brainstem   is   complicated   (there   is   no   point   avoiding   that   reality!).  
However,  two  factors  work  in  your  favor  as  you  study  its  features.  First,  important  general  principles  of  
embryology  will  help  you  understand  the  basic  plan  for  the  brainstem  (and  spinal  cord).  Second,  much  
of   the   complexity   of   the   brainstem   is   contributed   by   cell   groups   and   axon   tracts   that   will   not   be  
considered   in   this   course   (now,   that   comes   as   good   news!).   In   the   following   discussion,   the   general   plan  
of  organization  of  the  brainstem  is  presented  first.  Then,  the  cranial  nerve  nuclei  are  discussed  in  some  
detail.   An   understanding   of   their   functions   and   locations   is   essential   for   diagnosing   (and   treating)  
neurological  injury,  dysfunction  and  disease.  
It   would   be   convenient   if   each   subdivision   of   the   brainstem   were   sufficiently   homogeneous   along   its  
length   that   one   cross-­‐section   could   serve   as   a   ‘typical’   representative   for   the   entire   subdivision.  
However,   the   brainstem   changes   continuously   along   its   length—the   subdivision   into   three   parts   is  
somewhat   arbitrary.   As   a   compromise   between   examining   three   sections   (one   for   each   subdivision)   and  
hundreds,   eight   sections   of   the   brainstem   are   sketched   (to   scale)   in   Fig.   3.   At   this   stage,   it   is   not  
important  to  study  the  details;  we  will  come  back  to  them.  For  now,  three  points  should  be  taken  from  
the  figure.  
1. All   of   the   sections   are   shown   at   the   same   magnification   (a   little   less   than   two   times   actual   size).  
In   most   atlases   (including   Sylvius4   Online),   the   smaller   sections   are   magnified   more   than   the  
larger  ones,  and  it  is  easy  to  lose  sight  of  the  relative  proportions  of  the  different  subdivisions.  
2. The   cranial   nerve   nuclei   lie   in   the   tegmentum   of   the   brainstem   (gray   region   in   figure),   as   do  
many  of  the  major  ascending  and  descending  tracts.  
3. Just   as   in   the   spinal   cord,   the   nuclei   that   receive   sensory   inputs   via   the   cranial   nerves   are  
spatially   separate   from   those   that   give   rise   to   motor   output.   The   sensory   nuclei   are   located  
laterally  in  the  brainstem,  whereas  the  motor  nuclei  are  located  medially.  
Also  take  note  in  the  figure   that   although   the   sections   themselves   vary   greatly   in   size,   the   tegmentum   is  
approximately  the  same  size  in  all  of  them.  Much  of  the  effort  in  this  course  will  be  spent  on  learning  
the  organization  of  the  structures  in  the  tegmentum.  The  positions  of  the  cranial  nerve  nuclei  (and  also  
the   sensory   nuclei   known   as   the   dorsal   column   nuclei,   which   will   be   covered   in   a   later   tutorial)   are  
indicated   in   the   figure.   Motor   nuclei   are   represented   in   red   and   yellow,   indicating   somatic   motor   and  
visceral   motor   nuclei,   respectively;   sensory   nuclei   are   represented   in   blue;   important   tracts   are  
represented  in  unfilled  outline.  Note  that  the  tracts  are  external  to  the  sensory  and  motor  nuclei,  as  is  
the  case  in  the  spinal  cord.  
 
 
Fig.   3.   (next   page)   A.   Sagittal   view   of   the   brainstem   to   show   the   level   of   the   sections   in   part   B.   (The   small  
curved  arrow  indicates  the  location  of  the  median  aperture  through  which  cerebrospinal  fluid  escapes  from  the  
ventricular   system.)   B.   Sections   through   the   brainstem.   (Only   a   portion   of   the   cerebellum   is   included   in   the  
drawings  of  sections  4,  5  and  6).  (Illustration  by  N.B.  Cant)  
   

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 Cranial  Nerve  Nuclei  

Now,   let’s   look   at   the   location   of   the   cranial   nerve   nuclei   in   actual   transverse   sections   through   the  
brainstem.   In   the   sections   shown   in   the   remaining   figures,   the   photographs   of   the   sections   were  
prepared   according   to   standard   conventions   for   viewing   brainstem   sections:   gray   matter   is   light   gray  
and   white   matter   is   in   darker   shades   of   grade.   The   important   cranial   nerve   nuclei   are   colorized   and  
labeled.  The  locations  of  most  of  the  cranial  nerve  nuclei  listed  in  Tables  A2  &  A3  are  indicated  on  these  
sections.  
The  rostral  medulla  is  a  good  place  to  start  because  a  representative  of  each  motor  column  is  present  
(labeled  on  right  side  of  section),  and  most  of  the  sensory  nuclei  are  also  present  (labeled  on  left  side  of  
section).  Of  the  motor  nuclei,  the  hypoglossal   nucleus  is  closest  to  the  midline.  Next  to  it  is  the  dorsal  
motor  nucleus  of  the  vagus  nerve.   The  nucleus  ambiguus—true   to   its   name—is  difficult  to  delineate  in  
the   myelin-­‐stained   human   brain.   The   nucleus   of   the   solitary   tract   is   easy   to   spot,   because   it   is  
associated   with   an   isolated   myelinated   tract   (the   solitary   tract,   of   course)   that   terminates   in   the  
nucleus.  (The  fibers  in  the  tract  come  from  nerves  VII,  IX,  and  X.)  The  vestibular   nuclei  (a  collection  of  
discrete   nuclei)   are   large   and   can   be   seen   in   sections   through   much   of   the   medulla   and   pons.   The  
trigeminal  nucleus  in  the  medulla  is  known  as  the  spinal  trigeminal  nucleus.  Axons  travel  into  it  via  the  
spinal  trigeminal  tract,  which  is  just  lateral  to  the  nucleus.  
 
 
  Dorsal  m otor  
Vestibular   Nucleus  of  the  
nucleus  of  vagus  
  nuclei   solitary  tract  
Hypoglossal  
  nucleus  

 
 
 
 
 
Spinal  
 trigeminal  
nucleus  
 
Nucleus  
  ambiguus  
 
 
 
 
 
 

Fig.  4.  Cranial  nerve  nuclei  in  the  rostral  medulla.  (Section  shown  is  “9-­‐medulla”  in  Sylvius4  Online)  
   

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 Cranial  Nerve  Nuclei  

 
 
 
 
  Vestibular  
nuclei   Abducens  
  nucleus  

 
 
 
 
 
 
  Spinal  
trigeminal   Facial  
  nucleus   motor  
  nucleus  

 
 
 
 
 
 
 
 
 
 
 
Principal   Trigeminal  
  (chief   motor  
  sensory)   nucleus  
nucleus  of  the  
  trigeminal  
complex  
 
Fig.  5.  Cranial  nerve  nuclei  in  the  lower  pons  (top  section;  “7-­‐pons”  in  Sylvius4  Onilne)  and  upper  pons  (bottom  
section;  “6-­‐pons”  in  Sylvius4  Onine).  
   

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 Cranial  Nerve  Nuclei  

Three  motor  nuclei  can  be  identified  in  the  pons.  In  the  caudal  pons,  the  abducens  nucleus  occupies  the  
location   next   to   the   midline,   and   the  facial  motor  nucleus   is   located   ventral-­‐laterally   in   the   tegmentum.  
The  myelinated  axons  indicated  by  the  arrow  are  the  axons  that  are  leaving  the  seventh  motor  nucleus  
to   enter   the   seventh   nerve.   These   axons   loop   over   the   abducens   nucleus   before   they   exit   laterally,  
forming  what  is  known  as  the  ‘genu’  of  the  seventh  nerve.  Parts  of  two  nuclei  that  could  be  seen  in  the  
medulla  are  also  seen  here  in  the  caudal  pons—the  spinal  trigeminal  nucleus  and  the  vestibular  nuclei.  
The  final  motor  nucleus  in  the  pons  is  the  motor  nucleus  of  the  fifth  nerve,  also  known  as  the  trigeminal  
motor   nucleus,   which   is   rostral   to   the   seventh   motor   nucleus.   It   is   separated   from   the   chief   sensory  
nucleus  of  the  trigeminal  nerve  by  a  bundle  of  myelinated  fibers  which  are  either  entering  or  leaving  via  
the  fifth  nerve  (which  gets  to  these  nuclei  by  plunging  through  the  middle  cerebellar  peduncle).  
Three   motor   nuclei   can   be   identified   in   the   midbrain.   The   trochlear   nucleus   is   the   most   caudal   and   is  
very   small,   as   is   evident   in   the   section   shown   below   in   Fig.   6.   The   other   two   motor   nuclei   of   the  
midbrain  are  present  near  the  middle  of  the  midbrain.  There,  the  oculomotor  nucleus  occupies  a  medial  
position  in  the  dorsal  tegmentum  (Fig.   7).  You  can  see  some  of  the  myelinated  axons  that  are  forming  
the  third  nerve  medial  to  the  substantia  nigra  and  the  cerebral  peduncle  in  Fig.  7.  The  Edinger-­‐Westphal  
nucleus  lies  immediately  dorsal  to  the  oculomotor  nucleus  and  is  also  located  next  to  the  midline.  
 
  Trochlear  
nucleus  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Fig.  6.  Cranial  nerve  nuclei  in  the  caudal  midbrain.  (Section  shown  is  “3-­‐midbrain”  in  Sylvius4  Online)  

 
 
   

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 Cranial  Nerve  Nuclei  

 
 
  Edinger-­‐Westphal  
nucleus  
 
 
 
 
 
 
 
 
 
 
  Oculomotor  
nucleus  
 
 
Fig.  7.  Cranial  nerve  nuclei  in  the  middle  of  the  midbrain.  (Section  shown  is  “2-­‐midbrain”  in  Sylvius4  Online)  
 
Only   four   of   the   cranial   nerve   nuclei   are   not   identified   in   the   preceding   figures.   The   spinal   accessory  
nucleus  is  found  at  the  junction  of  the  caudal  medulla  and  the  spinal  cord  and  continues  caudally  into  
the  first  few  cervical  segments.  Very  few  people  in  the  world  know  just  where  the  superior  and  inferior  
salivatory  nuclei  are  located  (somewhere  in  the  dorsal  tegmentum  of  the  rostral  medulla/caudal  pons).  
The  cochlear  nucleus  is  located  just  at  the  junction  of  the  medulla  and  pons,  where  this  nucleus  wraps  
around   the   lateral   aspect   of   the   inferior   cerebellar   peduncle   (visible,   but   unlabeled   in   Sylvius4   Online,  
section  “8  –  Medulla”).  
You   should   now   be   able   to   identify   the   brainstem   subdivisions   from   which   each   section   is   taken.   You  
should   also   be   able   to   identify   each   of   the   cranial   nerve   nuclei   (except   for   the   four   mentioned   in   the  
preceding  paragraph).  To  consolidate  your  understanding  of  the  surface  anatomy  of  the  brainstem  and  
of   sections   through   it,   identify   the   point   at   which   each   cranial   nerve   enters   or   leaves   the   brain,   and  
determine   the   approximate   trajectory   of   the   axons   as   they   travel   to   or   from   this   point   to   the   cranial  
nerve  nuclei  with  which  they  are  connected.  By  the  end  of  this  learning  experience,  you  should  be  able  
to   view   a   cross   section   through   the   brainstem   and   identify   the   landmarks   that   characterize   the  
subdivision,  the  level  of  the  brainstem  from  which  it  was  taken  and  the  locations  of  the  cranial  nerves  
and  nuclei  that  are  present.  Make  sure  that  you  can  identify  all  of  the  structures  (in  bold)  discussed  in  
this  tutorial  and  identified  in  the  figures.  
 
   

11  
 Cranial  Nerve  Nuclei  

STUDY  QUESTION  
People  can  experience  “hemiparesis”  (unilateral  weakness)  for  many  reasons.  For  example,  hemiparesis  
can  result  from  damage  to  the  precentral  gyrus,  the  internal  capsule,  the  cerebral  peduncles,  the  
medullary  pyramids  or  the  spinal  cord  (all  structures  that  you  should  now  know  something  about!).  
If  you  saw  a  patient  that  was  weak  on  one  side  of  his  body  and  you  began  to  consider  the  location  of  the  
lesion,  which  of  the  following  actions  would  be,  arguably,  the  BEST  option  to  investigate  because  the  
resulting  action,  if  abnormal,  could  tell  you  most  precisely  where  the  lesion  was  located?  
A. ask  the  patient  to  point  to  your  nose  with  the  index  finger  of  his  weak  hand  
B. ask  the  patient  to  follow  your  finger  tip  with  his  gaze  as  you  moved  your  finger  from  side  to  side  
in  front  of  him  
C. ask  the  patient  to  stick  his  tongue  straight  out  at  you  
D. ask  the  patient  to  point  to  your  nose  with  the  index  finger  of  his  strong  hand  
E. ask  patient  to  stand  using  only  his  strong  leg  
 

12  
 Internal Anatomy of the Spinal Cord

Medical Neuroscience | Tutorial Notes

Internal Anatomy of the Spinal Cord

MAP TO NEUROSCIENCE CORE CONCEPTS1

NCC1. The brain is the body's most complex organ.

LEARNING OBJECTIVES
After study of the assigned learning materials, the student will:
1. Discuss the organization of gray matter in the spinal cord and the general functions associated
with the dorsal horn, ventral horn and intermediate gray matter.
2. Discuss the organization of white matter in the spinal cord and the general functions associated
with each column.

NARRATIVE
by Leonard E. White and Nell B. Cant
Duke Institute for Brain Sciences
Department of Neurobiology
Duke University School of Medicine

Introduction
After working through this tutorial, you should be able to discuss the organization of the various
components of gray matter and white matter in the spinal cord. Let’s begin by making sure that you
understand the basic layout of sensory and motor neurons in the spinal cord.
The central nervous system interacts with the outside world through primary sensory neurons, which
convey information from the body or its environment into the brain and spinal cord, and motor neurons,
which activate striated muscles and modulate the activity of cardiac and smooth muscles and glands
(see Fig. 1 below and/or Figure A1A2). The cell bodies of primary sensory neurons lie in the dorsal root
ganglia or the cranial nerve ganglia. Each neuron gives rise to a peripheral process, which receives
information either directly or through association with receptors, and a central process, which enters
the central nervous system and forms synapses with second order neurons. The cell bodies of somatic
motor neurons lie in clusters or nuclei within the central nervous system and give rise to axons that
innervate striated muscles in the body or head. You will also be introduced to other motor neurons that
are part of the visceral motor system (a.k.a., autonomic nervous system) and are indirectly responsible
for governing cardiac muscle, smooth muscle or glands.

1
Visit BrainFacts.org for Neuroscience Core Concepts (©2012 Society for Neuroscience ) that offer fundamental principles
about the brain and nervous system, the most complex living structure known in the universe.
2 Figure references to Purves et al., Neuroscience, 5th Ed., Sinauer Assoc., Inc., 2012. [click here]

1
 Internal Anatomy of the Spinal Cord

Fig. 1. Both the spinal cord and brainstem receive input

from primary sensory neurons; the cell bodies of these
neurons lie in sensory ganglia. In addition, both the spinal
cord and brainstem give rise to motor output to striated
muscles and to the autonomic ganglia (ANS, autonomic
nervous system; synonymous with visceral motor system).
(Illustration by N.B. Cant)

The internal anatomy of the spinal cord

The following brief discussion of the internal anatomy of the
spinal cord will introduce some of the general principles of
organization that also hold true for the brainstem. A
cross-section through the spinal cord is illustrated
schematically in Fig. 2. The gray matter forms the interior of
the spinal cord; it is surrounded on all sides by the white
matter. The white matter is subdivided into dorsal (or
posterior), lateral, and ventral (or anterior) columns. Each of
these columns contains bundles of axons related to specific
functions. For example, the lateral columns are made up
partly of axons that travel from the cerebral cortex to form synapses with motor neurons in the ventral
horn. The dorsal columns carry much of the ascending sensory information from mechanoreceptors
(more on these long pathways in later sessions).
The gray matter of the spinal cord is divided into dorsal and ventral (or posterior and anterior) ‘horns.’
The dorsal horn is the part of the gray matter that receives sensory information entering the spinal cord
via the dorsal roots of the spinal nerves. (Not all sensory fibers terminate in the dorsal horn of the spinal
cord; axons carrying sensory information from mechanoreceptors travel to the medulla before making
their first synapse in the pathway to conscious perception; they will be covered later.) The ventral horn
contains the cell bodies of motor neurons that send their axons out via the ventral roots to terminate on
striated muscles. Thus, one important general rule of organization is that neurons in the spinal cord that
process sensory information are spatially separate from motor neurons. (See Fig. 3 below and Table A1
of Neuroscience, 5th Ed., for more detail on the internal organization of spinal gray matter.)
As seen in a previous tutorial, the inputs and outputs of the spinal cord are arranged segmentally into
the 31 spinal nerves. However, the gray matter of the spinal cord is not obviously segmented. It can be
thought of as continuous columns (ventral horn) and layers (dorsal horn) of cells that run the length of
the cord, with important differences in the size of the dorsal and ventral horns at different levels. The
dorsal and ventral horns are largest where they supply the upper and lower limbs, because there are
significantly greater numbers of outgoing and incoming nerve fibers at those levels. There is also
variation along the length of the cord in the number of fibers in the columns of white matter (and,
therefore, in their relative size). The amount of white matter is greatest at cervical levels and least at
sacral levels. This is because ascending and descending fibers from and to all levels must pass through
the cervical cord. Such variations in the organization of specific gray matter and white matter
components along the length of the spinal cord are outlined in the chart on the next below.

2
 Internal Anatomy of the Spinal Cord

Fig. 2. Cross-section of the spinal cord at the cervical level. The general layout is the same at all levels of the
cord, although specific details differ from one level to the next (see chart below). (Illustration by N.B. Cant)

Internal features
Spinal Lateral Ventral
Dorsal Lateral Ventral White Gracile Cuneate Anterolateral
cord corticospinal corticospinal
segment
horn horn horn matter tract tract system
tract tract
Cervical
segments -- +++++ +++ +++ +++ + +++
(8)

Thoracic +
segments ++++ +++ ++ + ++
(12) --
Lumbar
segments -- +++ +++ -- ++ + ++
(5)

Sacral
segments -- ++ ++ -- + + +
(5)

Coccygeal
segment -- + + -- -- + +
(1)
Legend: indicates the structure’s presence; -- indicates the structure’s absence; +’s indicate the tract’s relative abundance
across segments.

3
 Internal Anatomy of the Spinal Cord

Fig. 3. Cross-sections through a lumbar segment of the human spinal cord. (A) Nissl stain highlighting cell
bodies. (B) Facsimile of a myelin stain highlighting (in dark tones) white matter. (images by L.E. White)

4
 Internal Anatomy of the Spinal Cord

STUDY QUESTION
Identify the MOST ACCURATE statement regarding the longitudinal organization of the spinal cord.
A. In the thoracic segments of the spinal cord, the volume of gray matter is greater than the
volume of white matter.
B. The sympathetic preganglionic neurons are localized to the thoracic segments of the spinal cord.
C. There is progressively more white matter in the spinal cord from one segment to the next in a
caudal progression.
D. The ventral horns achieve their greatest size in the thoracic segments of the spinal cord.
E. There is more neural circuitry in the gray matter of the thoracic segments than in the cervical or
lumbosacral enlargements of the spinal cord.

5
 Ventricles

Medical Neuroscience | Tutorial Notes

Ventricles

MAP TO NEUROSCIENCE CORE CONCEPTS1

NCC1. The brain is the body's most complex organ.

LEARNING OBJECTIVES
After study of the assigned learning materials, the student will:
1. Describe the distribution of the ventricular spaces in the forebrain and brainstem.

NARRATIVE
by Leonard E. WHITE and Nell B. CANT
Duke Institute for Brain Sciences
Department of Neurobiology
Duke University School of Medicine

Overview
Now that you have acquired a framework for understanding the regional anatomy of the human brain,
as viewed from the surface, and some understanding of the blood supply to both superficial and deep
brain structures, you are ready to explore the internal organization of the brain. In the next set of
tutorials from the brain anatomy lab, we will focus on the internal anatomy of the forebrain (recall that
the forebrain includes the derivatives of the embryonic prosencephalon). Given the complexity of the
brainstem and its importance for diagnosis and clinical practice, that portion of the brain will be
addressed in a separate set of tutorials. Here, the focus will be on the ventricular system of the human
central nervous system—the system of fluid-filled spaces in the human brain derived from the lumen of
the embryonic neural tube.

The ventricular system

As a point of emphasis for this tutorial, remember that the ventricles are the product of the
morphogenic events that bent, pinched and expanded the lumen of the embryological neural tube and
greatly increased the thickness and complexity of its walls (now that’s an understatement!). The
objective of this tutorial is to recognize the various compartments that constitute the ventricular system
of the adult brain. This will entail recognizing four principal ventricles, the paired lateral ventricles, the
third ventricle, and the fourth ventricle, as well as three narrow channels, the paired interventricular
foramina, and the single (midline) cerebral aqueduct.

1
Visit BrainFacts.org for Neuroscience Core Concepts (©2012 Society for Neuroscience ) that offer fundamental principles
about the brain and nervous system, the most complex living structure known in the universe.

1
 Ventricles

If you have a copy of Neuroscience, 5th Ed., begin by becoming familiar with Figure A232. If you have
access to a digital brain atlas, such as Sylvius4 Online, then open the atlas views in the coronal plane and
be prepared to step through the brain from anterior to posterior.
Begin passing through the brain from anterior to posterior and note the appearance of the frontal horn
of the lateral ventricle as it first appears. With your attention on the lateral ventricle, continue
sectioning and note the appearance of the temporal horn of the lateral ventricle in the medial temporal
lobe. Finally, note the caudal extension of the lateral ventricle as it penetrates the occipital lobe as the
occipital horn of the lateral ventricle.
Now, re-slice the forebrain in the axial (horizontal) plane from dorsal to ventral. Look for these same
compartments within the lateral ventricle. Do you notice how the lateral ventricle opens widely in its
central part or body, then appears more posteriorly in a region called the atrium before appearing more
anteriorly in the temporal lobe?
To appreciate the third ventricle, look for the narrow slit-like space along the midline at the medial base
of the diencephalon The interventricular foramina (of Monroe) provide the means for cerebrospinal
fluid (CSF) flow to from each lateral ventricle, where it is synthesized by choroid plexus, into the third
ventricle. Note that the two lateral ventricles are separated by a thin wall called the septum pellucidum.
Thus, CSF produced in the lateral ventricles first mixes in the third ventricle.
The third ventricle communicates with the fourth ventricle by means of a narrow channel through the
dorsal midbrain (mesencephalon) called the cerebral aqueduct. The cerebral aqueduct is a principal
landmark that will always help you identify transverse sections through the midbrain. From here,
continue sectioning through the brainstem in the caudal direction and note the gradual expansion of the
cerebral aqueduct as you enter the pons. By the middle of the pons, the cerebral aqueduct has fully
opened up into the fourth ventricle. This most caudal ventricle in the adult brain lies between the dorsal
surface of the pons and the large stalks of white matter (the cerebellar peduncles; “peduncle” means
stalk) that connect the cerebellum to the brainstem.

The circulation of CSF

From the foregoing account, it should be clear that CSF flows from the lateral ventricles, through the
interventricular foramina, into the third ventricle, through the cerebral aqueduct and into the fourth
ventricle. Actually, there is choroid plexus in each ventricle so some CSF is produced in each; but given
the large size of the lateral ventricles, these are the major produces of CSF. This may be surprising, but
the choroid plexus produces 2-3 times as much CSF every day as can be contained in the brain, the
cranial vault, and the spinal column. Thus, the entire volume present in the system is turned over
several times a day. Thus, obstruction of CSF flow results in an excess of cerebrospinal fluid in the
intracranial cavity, a dangerous condition called hydrocephalus (literally, “water head”) that can lead to
enlargement of the ventricles and compression of the brain. But how does the CSF leave the brain and
ultimately return to the venous vascular system?
Cerebrospinal fluid percolates through the ventricular system and flows into the subarachnoid space
through perforations in the thin covering of the fourth ventricle (through a midline foramen of
Magendie and two lateral foramena of Luschka). Once outside of the fourth ventricle, CSF flows in
between the pia mater and the arachnoid mater in the subarachnoid space. CSF eventually passes
through specialized structures called arachnoid villi or arachnoid granulations along the dorsal midline
of the forebrain (see Figure A21). These granulations are essentially one-way valves that communicate

2 th
Figure references to Purves et al., Neuroscience, 5 Ed., Sinauer Assoc., Inc., 2012. [click here]

2
 Ventricles

between the subarachnoid space and a prominent, midline dural sinus, called the superior sagittal
sinus. Thus, CSF is returned to the venous circulation via the system of dural sinuses that eventually
form the jugular veins in the base of the cranium.

STUDY QUESTIONS
Q1. Which structure produces cerebrospinal fluid?
A. choroid plexus
B. pineal gland
C. arachnoid granulations
D. cisterna magna
E. pituitary gland

Q2. Which statement below most accurately describes the components of the ventricular system
and/or the circulation of cerebrospinal fluid (CSF)?
A. CSF flows directly from one lateral ventricle through an aperture in the septum
pellucidum into the other lateral ventricle.
B. The third ventricle is lies posterior to the fourth ventricle.
C. The lateral ventricle is associated with the midbrain.
D. CSF circulates around the entire central nervous system in the subarachnoid space.
E. CSF flows into the subarachnoid space via apertures in the third ventricle.

3
 Internal Capsule and Deep Gray Matter

Medical Neuroscience | Tutorial Notes

Internal Capsule and Deep Gray Matter

MAP TO NEUROSCIENCE CORE CONCEPTS1

NCC1. The brain is the body's most complex organ.
NCC3. Genetically determined circuits are the foundation of the nervous system.

LEARNING OBJECTIVES
After study of the assigned learning materials, the student will:
1. Identify major white matter and gray matter structures that are apparent in sectional views of
the forebrain, including the structures listed in the chart and figures in this tutorial.
2. Describe and sketch the relations of the deep gray matter structures to the internal capsule in
coronal and axial sections of the forebrain.
3. Describe the distribution of the ventricular spaces in the forebrain and brainstem.

NARRATIVE
by Leonard E. WHITE and Nell B. CANT
Duke Institute for Brain Sciences
Department of Neurobiology
Duke University School of Medicine

Overview
Now that you have acquired a framework for understanding the regional anatomy of the human brain,
as viewed from the surface, and some understanding of the blood supply to both superficial and deep
brain structures, you are ready to explore the internal organization of the brain. This tutorial will focus
on the sectional anatomy of the forebrain (recall that the forebrain includes the derivatives of the
embryonic prosencephalon). As you will discover, much of our framework for exploring the sectional
anatomy of the forebrain is provided by the internal capsule and the deep gray matter, including the
basal ganglia and the thalamus. But before beginning to study this internal anatomy, it will be helpful to
familiarize yourself with some common conventions that are used to describe the deep structures of the
central nervous system.

Some terminology and general principles

The next few pages contain definitions and illustrations of some commonly used neuroanatomical

1
Visit BrainFacts.org for Neuroscience Core Concepts (©2012 Society for Neuroscience ) that offer fundamental principles
about the brain and nervous system, the most complex living structure known in the universe.

1
 Internal Capsule and Deep Gray Matter

terminology. They may be useful for reference as you study the material in this and the related
neuroanatomical tutorials.
The simplest classification of central nervous tissue is white matter and gray matter (Figure 1). The gray
matter (so-named because it looks grayish in fresh specimens) is made up of neuronal cell bodies, their
dendrites, and the terminal arborizations of both local axons and those from distant sources. The
dendrites and the axons that form synapses with them are sometimes referred to as “neuropil.” The
white matter is made up of the axons that connect separated areas of gray matter. The myelin that
ensheathes many of these axons gives the white matter its glistening white appearance. Note that an
individual neuron can contribute to both gray and white matter. Axons projecting from one part of the
brain to another usually group together in bundles. Likewise, neurons that serve similar functions often
form clusters.

Gray matter

White matter

Gray matter

Figure 1. Gray and white matter in the central nervous system. Left, Drawings depicting the composition of
both types of neural tissue (Illustration courtesy of Pyramis Studios, Durham NC). Right, Drawing of the
organization of gray and white matter in the brain and spinal cord; cortex, basal ganglia, nucleus and cell
column are all examples of gray matter in the central nervous system. (Illustration by N.B. Cant)

Common terms used to refer to white matter bundles and gray matter clusters:
Terms used to refer to gray matter
Column
Cortex (plural: cortices; L., bark)
Ganglion (plural: ganglia; Gr., swelling)
Layer
Nucleus (plural: nuclei)

2
 Internal Capsule and Deep Gray Matter

Terms used to refer to white matter

These five terms are used to refer to bundles of axons:
Column
Fasciculus (L., fascia, band or bundle)
Funiculus (L., funis, cord)
Lemniscus (L. from Gr., lemniskos, fillet)
Tract
These terms also refer to bundles of axons, but they are usually used to refer to bundles that
can be seen from the surface of the brain:
Brachium (L., arm)
Peduncle (L., pes, foot, stalk)
These terms refer to the crossing of axons from one side of the CNS to the other. A commissure
contains axons crossing from one location to its counterpart on the other side. A decussation
contains axons that travel to a contralateral location different from their origin.
Commissure (L., joining together)
Decussation (L., decussare, to cross in the form of an “X”)
Many nuclei and tracts in the central nervous system are much longer than they are wide, calling to
mind a column. (Note that the word ‘column’ is used to refer to both white matter and gray matter.)
Although the terms that refer to white matter structures are not used interchangeably, they all refer to
essentially the same constituent—axons (often in a compact bundle) connecting one area of gray matter
to another.
You will also encounter the following terms used to refer to general regions of the central nervous
system:
tectum (L., roof)—used to refer to brainstem structures located dorsal to the ventricular system. In
mammals, this term has become synonymous with the dorsal midbrain.
tegmentum—this term refers to structures that form the core of the brainstem (Figure 2). It can be
thought of (very loosely) as the part of the brainstem that is most like the spinal cord in the sense
that the cell groups in the tegmentum have functions similar to those of cell groups in the spinal
cord. For the most part, the structures that lie outside the tegmentum have no counterparts in the
spinal cord.
base—the ventral aspect of the brain. The term ‘basal’ is synonymous with ‘ventral.’
floor, wall—usually used with respect to structures that bound the ventricles (e.g., the floor of the
fourth ventricle corresponds to the part of the pons and medulla that forms the ventral boundary of
the ventricle).

3
 Internal Capsule and Deep Gray Matter

Figure 2. Structures in the core of the

brainstem make up the tegmentum. It
includes the cranial nerve nuclei, most long
tracts, and loosely arranged groups of
neurons known collectively as the reticular
formation. (Illustration by N.B. Cant)

The large number of terms used to refer to similar

structures may seem annoying, but it is not unlike the case
in non-medical English usage. Consider, for example, the
many terms that refer to roadways (street, avenue,
boulevard, interstate, path, road, highway, etc.).

4
 Internal Capsule and Deep Gray Matter

Internal anatomy of the forebrain

For the rest of this tutorial, we will discuss the appearance of sections through the forebrain, so that you
can learn to identify the structures that are not visible on a surface view. The anatomy of the forebrain
as seen in sections is relatively simple; however the geometry of some of these deep structures can be a
challenge to appreciate. For an example, if you have Neuroscience 5th Ed., note the locations of the
hippocampal formation and the lateral ventricle in the illustration of a partially dissected hemisphere in
Figure A132. You will soon learn why these structures appear where they do. In brief, the hippocampus
and other deep forebrain structures follow the course of the lateral ventricle into the temporal lobe. The
hippocampus (one component of the hippocampal formation) lies in the ‘floor’ of the lateral ventricle in
the temporal lobe. The fornix is a bundle of axons that arises mainly in the hippocampus and essentially
travels to the diencephalon along this same path (i.e., following the course of the lateral ventricle).
As you work through the remainder of this tutorial—and hopefully, as you explore the brain on your
own in a digital brain atlas such as Sylvius4 Online, be sure to recognize and locate the following
structures on sections cut in any of the three standard anatomical planes:

Gray Matter White Matter Ventricle

Cortical/corticoid structures:
Corpus callosum
Telencephalon cerebral cortex; hippocampus; amygdala
Anterior commissure Lateral
(cerebral Basal ganglia (deep structures):
Fornix ventricle
hemispheres) caudate nucleus, putamen, nucleus
Internal capsule
accumbens, globus pallidus
Thalamus Third
Diencephalon Fornix
Hypothalamus ventricle

Let’s approach our study of internal forebrain anatomy with the cerebral cortex. The cerebral cortex is a
thin layer of gray matter that covers the entire surface of the hemispheres. Most of the cortex that is
visible from the surface in humans is known as neocortex, cortex which is made up of six layers of
neurons. Phylogenetically older cortex, which has fewer cell layers, is found on the inferior surface of
the temporal lobe, separated from neocortex by the rhinal fissure (Figure 3). The cortex with the fewest
layers (three) is known as the hippocampus (paleocortex of the parahippocampal gyrus). The
hippocampus is the medial edge of temporal cortex that becomes double-folded into the medial aspect
of the temporal lobe; it is visible only in dissected brains or in sections. It is worth remembering that the
entire cerebral cortex is derived from the walls of the largest and most anterior swelling of the
embryonic brain, the prosencephalon. Thus, despite its deep sulci and fissures and phylogenetic
divisions, the entire cerebral cortex in one hemisphere is a continuous sheet of neural tissue.

2 th
Figure references to Purves et al., Neuroscience, 5 Ed., Sinauer Assoc., Inc., 2012. [click here]

5
 Internal Capsule and Deep Gray Matter

Figure 3. Close-up view of the ventral-medial surface of the temporal lobe to show the parahippocampal gyrus
and related sulci. The rhinal fissure separates the lateral neocortex from the medial paleocortex. The medial
protuberance in the parahippocampal gyrus is called the uncus, which is cortical division of the posterior
amygdala.

6
 Internal Capsule and Deep Gray Matter

The cortex is made up of neuronal cell bodies, their dendrites, and the terminal arborizations of axons
coming from the thalamus and other sources, mainly from other neurons in the cerebral cortex. Indeed,
many neurons in the cortex send axons that travel some considerable distance in the central nervous
system to make synaptic connections with other neurons. Axons that enter and leave the cortex form
the white matter that makes up a large part of the hemispheres. We often speak of axons as though
they were moving, using words such as ‘entering,’ ‘leaving,’ ‘descending,’ ‘traveling,’ ‘projecting,’ etc. Of
course, their place is fixed in the adult, and what we are actually referring to are the directions in which
action potentials normally propagate along the axons.
Buried deep within the hemispheres are the basal ganglia (Figure 4), which are large gray matter
structures concerned with modulating thalamic interactions with the frontal lobe. (The term ‘ganglion’ is
not usually used for clusters of neurons inside the central nervous system; this is an exception.) The
basal ganglia lie partly rostral and partly lateral to the diencephalon (refer to the chart on page 1 for
their embryonic relations). They can be divided into four main structures: the caudate, the putamen,
the nucleus accumbens, and the globus pallidus.

Nucleus
accumbens

Figure 4. The basal ganglia and thalamus drawn with all of the cortex and white matter of the hemispheres
stripped away; viewed from the side (refer to the inset for orientation). The head of the caudate is in the
frontal lobe; its body lies just dorsal to the thalamus, and its tail descends into the temporal lobe. The amygdala
is an additional structure deep in the anterior temporal lobe that is situated near the anterior tip of the
caudate’s tail (but it really is not part of the caudate as this illustration might imply). The nucleus accumbens is
located at the anterior, inferior junction of the caudate nucleus and putamen. The globus pallidus is hidden
from view by the putamen, which is lateral to it. The groove between the putamen and the caudate—and
between the putamen (and globus pallidus) and the thalamus—is occupied by a massive fan-like array of white
matter, called the internal capsule (omitted from this depiction to illustrate the body of the caudate nucleus
and the thalamus). (illustration courtesy of Pyramis Studios, Durham NC)

7
 Internal Capsule and Deep Gray Matter

Structurally and functionally, the caudate, putamen and nucleus accumbens are similar, and they are
often referred to collectively as the striatum, because of the stripes or “striations” of gray matter that
run through a prominent bundle of white matter (the internal capsule) that otherwise separates the
caudate from the putamen. (The caudate and putamen are also called the “neostriatum” to emphasize
their evolutionary and functional relation to neural circuits in the neocortex.) Ventral to the caudate and
putamen are additional divisions of the striatum, which are important for understanding motivated
behavior and addiction. The most prominent of these structures in this so-called ventral striatum is the
nucleus accumbens.
These three divisions of the striatum receive inputs from different portions of the telencephalon that
define the functional roles of each striatal division. In general terms, the striatum (and the circuits
through the basal ganglia that begin here) regulates movement, with the three divisions of the striatum
governing different domains of movement. Thus, it should be instructive to remember that:
 the putamen is concerned with the regulation of bodily movement;
 the caudate nucleus (especially its large anterior ‘head’) regulates movement of the mind and
eyes (which often indicate what we are thinking about); and
 the nucleus accumbens is concerned with movement of emotion or motivated behavior.
Obviously, we are speaking of the concept of movement in loose terms. Nevertheless, it is important to
recognize that each striatal division (and the distinct circuits through the basal ganglia that derive from
each) share common structural and functional motifs that help explain their contribution to the
modulation of behavior. Each circuit is involved in the initiation or suppression of some program for
behavior. To accomplish these functions, each division of the striatum projects to some division of the
pallidum; the globus pallidus is the largest division of the pallidum and it receives input mainly from the
putamen. The pallidum in turn regulates thalamo-cortical interactions. A full consideration of basal
ganglia circuitry is beyond the scope of this tutorial; but these important circuits will be considered
elsewhere in the course when we explore in some depth the functions of the basal ganglia.
Now let’s turn our attention from gray matter to white matter. There are three bundles of axons in the
hemisphere that have already been identified on mid-sagittal views: the corpus callosum, anterior
commissure and fornix (see the tutorial, Medial Surface of the Brain). One additional system of axonal
fibers should now be appreciated. Many of the axons entering or leaving the cortex do not assemble
into compact bundles, except in the vicinity of the thalamus and the basal ganglia, where they form a
structure known as the internal capsule. The internal capsule lies just lateral to the diencephalon, and as
mentioned briefly above, a portion of it separates the caudate from the putamen. Many of the axons in
the internal capsule terminate or arise in the thalamus. Other systems of axons descending from the
cortex, course through the internal capsule, and continue past the diencephalon to enter the cerebral
peduncles of the midbrain. Between the cortex and the internal capsule, the axons of the white matter
are not so tightly packed; they are sometimes called the ‘corona radiata’, a reference to the way they
appear to radiate out from the compact internal capsule to reach multiple areas of cortex. (Individual
groups of axons may also be indicated in this way. For example, you will hear reference to the visual
radiations or the auditory radiations, axons that travel from the thalamus to the visual and auditory
cortices, respectively.) We will return to the internal capsule in relation to the important deep gray
matter structures as we consider cross-sectional views through the forebrain.
There are several other bundles of axons that run through the white matter of the forebrain
longitudinally in each cerebral hemisphere, connecting different cortical areas (associational white
matter); but you need not be concerned with identifying them now.

8
 Internal Capsule and Deep Gray Matter

That is almost it for structures in the cerebral hemispheres!

There are two other gray matter structures you should know. One is a group of complex nuclei, known
as the basal forebrain nuclei, which have become associated with the signs and symptoms of diseases
such as Alzheimer’s disease (see Figure 8). Like the basal ganglia, the basal forebrain nuclei are made up
of clusters of cells (rather than layers); but unlike the basal ganglia, these clusters are much smaller and
typically much less compact. They are located ventral to the anterior commissure and below the basal
ganglia, between the ventral striatum and the hypothalamus.
The other structure you should know is the amygdala, which is a large mass of gray matter buried in the
anterior-medial part of the temporal lobe, anterior to the lateral ventricle and the hippocampus (see
Figure 9). The amygdala is an important component of ventral-medial forebrain circuitry and it is
involved in the experience and expression of emotion. It was once classified as part of the basal ganglia;
however, it is structurally and functionally heterogeneous, with systems of neurons and intrinsic
connections that are comparable to those in striatum and the cerebral cortex. We will discuss the
amygdala and its connections within the limbic forebrain in some depth in later tutorials (see The
Amygdala and Hippocampus and Neurobiology of Emotion).
There is one slight complication that you will encounter as you begin to identify the structures of the
forebrain in sections. Sometimes you see the same structures twice in the same section in the same
hemisphere. To understand why this is so, refer to Figures 5 & 6.

Figure 5. A. During development, the human cerebral hemispheres grow markedly in the posterior and ventral
directions, forming the temporal lobe. As the temporal lobe grows, the hemisphere appears to rotate forward,
beginning to form a shape something like a horseshoe. Deeper structures in the hemispheres follow this
pattern of growth so that in the adult brain they also form an arch or horseshoe shape. B. The lateral ventricle
curves into the temporal lobe. (The part in the temporal lobe is referred to as the inferior or temporal horn.) C.
The caudate nucleus of the basal ganglia has a ‘tail’ which curves into the temporal lobe (cf. Figure 4). D. The
corpus callosum curves slightly but does not continue into the temporal lobe. The hippocampus is located in
the temporal lobe and gives rise to the fornix which arches over the diencephalon to enter it at its anterior end.
The lines in B-D indicate planes of section (coronal and horizontal) that cut twice through the structures
shown. (Illustration from N.B. Cant)

9
 Internal Capsule and Deep Gray Matter

The diencephalon comes to lie medial to the hemispheres. The thalamus is the largest subdivision of the
diencephalon (see Figure 6). It is egg-shaped and is made up of many subdivisions, some of which we
shall identify later. The hypothalamus lies ventral to the thalamus. Anterior to the hypothalamus is the
optic chiasm. (Clinically, the close physical proximity of the chiasm to the pituitary gland is very
important, since a combination of visual and endocrine problems is a strong indication of a pituitary
tumor.) The mammillary bodies are a part of the hypothalamus lying in its caudal part just at its junction
with the midbrain.

Figure 6. Brainstem and

thalamus drawn with the
cerebral hemispheres and
cerebellum removed. This
figure highlights the sharp
bend in the long axis of the
central nervous system that
occurs at the junction of
the midbrain and
diencephalon. This causes
the dorsal diencephalon to
lie almost at a right angle to
the dorsal midbrain. (The
epithalamus, represented
here by the pineal gland, is
the most dorsal part of the
diencephalon, but when the
brain is viewed from the
side as here, it appears to
lie deep, since the lateral
parts of the dorsal thalamus
expand greatly in size.
(Illustration from N.B. Cant)

Internal capsule and deep gray matter

One of the most difficult challenges in human brain anatomy is gaining an appreciation for the 3D
arrangement of deep gray and white matter within the forebrain. But be encouraged! There is a
principled means of simplifying this challenge. You must first understand the positional relations among
the major components of the basal ganglia (caudate nucleus, putamen, nucleus accumbens, globus
pallidus), thalamus, and the internal capsule. Then, you should recognize how the lateral ventricle fits in.
Once you do so, you can interpret any section through the forebrain in any plane of section, be it a
standard anatomical plane or an oblique plane.
Here’s the key to framing your 3D understanding: the deep gray matter structures identified above are
always found on one side of the internal capsule or the other. Specifically …
the caudate nucleus and the thalamus are medial to the internal capsule; and the
putamen and globus pallidus are lateral to the internal capsule.
These relations reflect the course of the outgrowing axons that formed the internal capsule in fetal

10
 Internal Capsule and Deep Gray Matter

development as they navigated through the anlage of deep gray matter in the embryonic brain. As you
carefully inspect sections through the forebrain (in the next few pages and in Sylvius4 Onilne), note the
appearance of the internal capsule and the deep gray matter. There are several additional details to
observe and learn:
(1) the caudate nucleus, putamen and nucleus accumbens become continuous around the
rostral margin of the internal capsule;
(2) the globus pallidus is a relatively small structure located near the middle of the basal
ganglia;
(3) the globus pallidus is located between the internal capsule and the putamen;
(4) the thalamus occupies a more posterior volume of brain-space than the bulk of the
basal ganglia;
(5) the caudate nucleus has a long “tail” that follows the course of the lateral ventricle into
the temporal lobe (see again Figures 4 & 5).
(6) the anterior limb of internal capsule separates the head of the caudate from putamen
and globus pallidus, and the posterior limb of internal capsule mainly separates
thalamus from globus pallidus
So now that you are primed to interpret the internal anatomy of the forebrain, careful inspect the
images of coronal sections on the following pages (and in the video tutorial) and identify each of the
structures and relations numbered (1) to (6) above.

Coronal sections through the brain

The five coronal sections through the brain shown, beginning on the next page (Figures 7–11), were
taken from Sylvius4 Online and should resemble the brains that were shown in the tutorial. Remember,
areas with little or no myelin appear dark and are considered gray matter, and areas containing
myelinated axons appear light and are called white matter.

11
 Internal Capsule and Deep Gray Matter

Figure 7. This first section is anterior to the region where the anterior commissure crosses the midline so only
the hemispheres are present, and the diencephalon is not seen. The basal ganglia, which form part of the
hemispheres, are very large here in the frontal lobes. Key: 1. Cerebral cortex of the frontal lobe; 2. Corpus
callosum; 3. Lateral ventricle; 4. Septum pellucidum (which separates the two lateral ventricles); 5. Caudate
nucleus (which bulges into the lateral ventricle); 6. Anterior limb of internal capsule (which separates the
caudate and putamen from one another; recall that the ‘stripes’ of gray matter stretching across the internal
capsule between these two nuclei are the inspiration for the term ‘striatum’); 7. Putamen; 8. Nucleus
accumbens. (Image is “Coronal 3” from Sylvius4 Online)

12
 Internal Capsule and Deep Gray Matter

Figure 8. The second section in the series is at the level where the anterior commissure crosses the midline.
Locate the caudate and putamen and the globus pallidus. Also find the internal capsule, the lateral ventricles,
the corpus callosum, and the fornix. (You see the fornix only once on each side in this section. Why?) You can
also see the optic chiasm. Nuclei of the basal forebrain are located in the inferior frontal lobe (below the
anterior commissure). Key: 1. Globus pallidus; 2. Putamen; 3. Caudate; 4. Cortex of temporal lobe; 5. region of
basal forebrain nuclei; 6. Optic chiasm; 7. Anterior commissure; 8. Fornix; 9. Internal capsule; 10. Lateral
ventricle; 11. Corpus callosum. (Image is “Coronal 4” from Sylvius4 Online)

13
 Internal Capsule and Deep Gray Matter

13

Figure 9. The third section in the series lies about halfway through the brain. Since this section lies posterior to
the anterior commissure, the diencephalon appears next to the midline. The thalamus is separated from the
putamen and globus pallidus by the internal capsule. The hypothalamus lies ventral to the thalamus. Lateral to
the hypothalamus is the area known as the subthalamus. The cortex in the medial aspect of the temporal lobe
is known as the hippocampus, which is emerging just inferior to the posterior portion of the amygdala. Key: 1.
Internal capsule; 2. Thalamus; 3. Hypothalamus (mammillary body); 4. Subthalamus; 5. Hippocampus; 6.
Caudate; 7. Putamen, 8. Globus pallidus; 9. Corpus callosum; 10. Fornix; 12. Lateral ventricle; 13 (posterior)
amygdala. (Image is “Coronal 5” from Sylvius4 Online)

14
 Internal Capsule and Deep Gray Matter

13

Figure 10. In this section, you can see the transition from the diencephalon to the midbrain of the brainstem.
(Some of the structures of the midbrain are labeled in the figure.) In the forebrain, some of the same
structures that were seen in more anterior sections can still be identified, although the basal ganglia have
almost disappeared. Only a small portion of the caudate nucleus can still be seen. One important part of the
thalamus, the lateral geniculate nucleus, is seen. Key: 1. Internal capsule; 2. Corpus callosum; 3. Thalamus; 4.
Lateral geniculate nucleus (part of the thalamus); 5. Hippocampus; 6 & 7. Lateral ventricle; 8. Fornix; 9.
Caudate; 10. Midbrain; 11. Substantia nigra (pars compacta); 12. Cerebral peduncle; 13. Ventral tegmental area.
(Image is “Coronal 5” from Sylvius4 Onilne)

15
 Internal Capsule and Deep Gray Matter

Figure 11. The most posterior section in the series is cut through the parietal lobes. Since the cut is posterior to
the corpus callosum, the two hemispheres are not connected to each other. In the forebrain, only the gray and
white matter and the posterior horn of the lateral ventricle are seen; none of the deep gray matter structures
are present. The section also passes through the brainstem. This part of the brainstem is known as the pons; it
lies ventral to the cerebellum. Key: 1. Lateral ventricle (posterior or occipital horn); 2. Middle cerebellar
peduncle; 3. Superior cerebellar peduncle; 4. Cerebellum (cerebellar cortex); 5. Fourth ventricle (most rostral
recess continuous with the cerebral aqueduct). (Image is “Coronal 5” from Sylvius4 Online)

16
 Internal Capsule and Deep Gray Matter

Optional exercise—modeling deep gray matter

Now that you have some experience with the sectional anatomy of the forebrain and a growing
appreciation for the relations of deep gray matter structures in brain-space, you are ready to get your
hands dirty. No sequence of neuroanatomical study is complete until learners are challenged to build or
model their own brain. Obtain a set of colored modeling clay or make your own (several simple recipes
are available on the www); five colors would be best, with one being white. Your goal will be to
construct a simple, but accurate model of the spatial relations in the brain that you discovered in
working through this tutorial. In particular, construct a clay (dough) model of the major components of
the basal ganglia, thalamus and internal capsule, as described on pp. 10-11, with special attention to
the six numbered points of detail.
How to start? Begin by constructing the internal capsule: flatten out a white (for white matter, of
course) lump of clay into an elongated fan shape. In the brain, the wide end of the fan (called the corona
radiata) penetrates into the subcortical white matter and the narrow end penetrates the diencephalon
and brainstem, where it forms the cerebral peduncle and, eventually, the medullary pyramid; the basal
ganglia and thalamus reside near the middle of the fan. Next, add a colored lump of clay for the globus
pallidus (but on what side of the internal capsule, lateral or medial?). Then, encompass your ‘faux’
globus pallidus with the putamen and fashion at least the rostral and dorsal portions of the caudate
nucleus. When ready to be more ambitious, try creating a more complete caudate nucleus that includes
its temporal tail. Finally, add an egg-shaped lump for the thalamus (remember its position relative to the
internal capsule?). How does it look … anything like Figure 4? Don’t worry if your first attempt(s) are
less than edifying. What is most important about this exercise is the visualization of spatial relations that
comes from wrestling with both substance (modeling clay) and abstraction (imagined brain-space).
One additional tip for this modeling exercise: Sylvius4 Online contains illustrations and an interactive
virtual model of a standard brainstem model that is often used in neuroanatomical laboratories
(including ours). This model includes the diencephalon, basal ganglion and internal capsule; refer to this
model and interact with the “Atlas extras” feature (available via the folder in the navigation window in
the upper left) for additional views of the relation among these structures.
Now that you have in front of you a clay model of the deep gray matter of the human brain, try actually
sectioning your model in one of the three standard neuroanatomical planes (the coronal plane is a
good starting plane for deconstruction). This should be easily done with a standard kitchen knife or a
thin wire. Assuming the clay (dough) is of the proper consistency and has survived sectioning, do you
recognize the spatial relations among your modeled gray matter structures that you discovered in the
human brain? Try comparing different planes of section through your model with sectional views of the
digital brain in Sylvius4 Online. You might even try re-attaching your sections with a little gentle
kneading and then re-sectioning in an orthogonal plane (try axial next).
With some persistence and patience, working through this exercise will foster a more cogent
understanding of 3D relations within the deepest substratum of the human forebrain. You might even
want to snap a photograph of your model and post it to the Discussion Forum!

17
 Internal Capsule and Deep Gray Matter

STUDY QUESTIONS
Q1. Which pair of structures is located on the medial side of the internal capsule?
A. caudate nucleus & thalamus
B. nucleus accumbens & putamen
C. putamen & globus pallidus
D. amygdala & hippocampus
E. putamen & insula

Q2. Which pair of structures is located on the lateral side of the internal capsule?
A. globus pallidus & caudate nucleus
B. pineal gland & mammillary body
C. third ventricle & body of lateral ventricle
D. caudate nucleus & thalamus
E. putamen & globus pallidus

18
 Overview of Neural Signaling

Medical Neuroscience | Tutorial Notes

Overview of Neural Signaling

MAP TO NEUROSCIENCE CORE CONCEPTS1

NCC2. Neurons communicate using both electrical and chemical signals.

LEARNING OBJECTIVES
After study of the assigned learning materials, the student will:
1. Differentiate the resting membrane potential from the action potential.
2. Describe one means for encoding information in the activity of neurons.

TUTORIAL OUTLINE

I. Introduction to neural signaling

A. ELECTRICAL SIGNALING IS THE FUNDAMENTAL NEURONAL PROCESS THAT UNDERLIES ALL ASPECTS OF
BRAIN FUNCTION

B. neurons process and transmit information via the generation of electrical signals
1. neurons are intrinsically poor conductors of electricity
2. however, neurons develop mechanisms for the generation of electrical signals
3. electrical signals are based upon the flow of ions across plasma membranes
C. overview of the electrical signals of nerve cells (see Figure 2.22)
1. neurons have a means of generating a steady-state electrical potential across
their plasma membrane, called a resting membrane potential; this potential is
negative, usually in the range of –40 to –90 mV (thus, the neuronal membrane is
said to be negatively “polarized”)
2. when an electrical stimulus is applied to a neuron (either via electrical signals of
other neurons or artificially by a stimulating microelectrode), the resting
membrane potential may become hyperpolarized (= more negative) or
depolarized (= less negative)
3. if a depolarizing stimulus is strong enough, a very large, explosive depolarizing
event may suddenly occur and the membrane potential may actually become

1
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1
 Overview of Neural Signaling

positive for a brief period of time; this sudden, all-or-none electrical event is
called an action potential
a. the membrane potential at which an action potential is triggered is
called threshold
b. the action potential is said to be “all-or-none” because it either occurs
at full amplitude or not at all
c. if a supra-threshold stimulus is very strong, more than one action
potential may be elicited
d. thus, the strength of a stimulus may be encoded by the number of
action potentials elicited (not the amplitude of the action potential)
4. action potentials are “propagated” along axons until the end of the axons is
reached where a special junction, called a synapse (located at a synaptic
terminal), exists for the purpose of communicating the electrical signal from one
axon to another cell (usually to the dendrites or soma of another neuron)

II. Ionic movements produce electrical signals

A. Two molecular mechanisms account for the generation of electrical signals in nerve cells
(see Figure 2.4): ion pumps and ion channels
1. there are differences in the concentrations of specific ions across the nerve cell
membrane; these concentration gradients are generated by ion pumps
2. the nerve cell membrane is selectively permeable to certain ions; the passage
of ions across the membrane occurs via the opening of ion channels
B. thus, PUMPS ESTABLISH THE CONCENTRATION GRADIENTS THAT PROVIDE THE “DRIVING FORCE” FOR THE
DIFFUSION OF THE IONS THROUGH CHANNELS

STUDY QUESTION
Pinch yourself (really!). Now pinch yourself again, only this time, apply just a little more pinch so that
you notice that this one is stronger. So what’s the difference between the first gentle pinch and the
second stronger pinch?
A. The first pinch generated passive responses in the sensory axons of the relevant spinal nerve,
while the second pinch generated action potentials.
B. The second stronger pinch generated more action potentials in the sensory axons of the
relevant spinal nerve, compared to the first weaker pinch.
C. The second stronger pinch generated larger action potentials in the sensory axons of the
relevant spinal nerve, compared to the first weaker pinch.

2
 Overview of Neural Signaling

Medical Neuroscience | Tutorial Notes

Ionic Basis of the Resting Membrane Potential

MAP TO NEUROSCIENCE CORE CONCEPTS3

NCC2. Neurons communicate using both electrical and chemical signals.

LEARNING OBJECTIVES
After study of the assigned learning materials, the learner will:

3. Describe the concept of electrochemical equilibrium and relate this concept to the resting
membrane potential of neurons.
4. Explain why the permeability of the neuronal plasma membrane at rest to K+ and the
concentration gradient of this ion across the neuronal plasma membrane account for the resting
membrane potential of neurons.
5. Use the Nernst equation to predict the resting membrane potential of neurons given knowledge
of the concentration gradients of permeant ions.

TUTORIAL OUTLINE

I. Introduction: ionic movements produce electrical signals

B. Two molecular mechanisms account for the generation of electrical signals in nerve cells
(see Figure 2.44): ion pumps and ion channels
3. there are differences in the concentrations of specific ions across the nerve cell
membrane; these concentration gradients are generated by ion pumps
4. the nerve cell membrane is selectively permeable to certain ions; the passage
of ions across the membrane occurs via the opening of ion channels
5. thus, PUMPS ESTABLISH THE CONCENTRATION GRADIENTS THAT PROVIDE THE “DRIVING
FORCE” FOR THE DIFFUSION OF THE IONS THROUGH CHANNELS

C. Consider a model neuronal system at rest (see Figure 2.5A & B)

1. an electrochemical equilibrium will be established when the inside of cells
becomes just negative enough to impede the further (net) outflow of K+ (in this
case, electrochemical equilibrium is established at –58 mV)
2. “leak” of K+ out of neurons accounts for the resting membrane potential

3
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4 th
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3
 Overview of Neural Signaling

a. factors needed for the generation of a bioelectric potential:

i. concentration gradient
ii. selectively permeable membrane
b. these factors are satisfied in neurons at rest for K+ (see Figure 2.4)
3. very few ions need to flow across the plasma membrane to generate a
membrane potential
a. concentrations of permeant ions are relatively unchanged by signaling
b. overall electrical neutrality is maintained because very few ions flow
across permeable membranes and, in this case, Cl- provides the
opposite charge to balance the positive charge of K+
c. the separation of charge that accounts for the resting membrane
potential is confined to the inner and outer surfaces of the membrane

III. view an online animation that accompanies Neuroscience, 5th. Ed., Chapter 2: Animation 2.1 The
Resting Membrane Potential [click here]

IV. Predicting the membrane potential

A. the Nernst equation
1. accounts for the equilibrium potential of a plasma membrane that is selectively
permeable to one ionic species
Ex = 58 log [X]o
z [X]i

Ex equilibrium potential for any ion

z valence of the permeant ion (electrical charge)
[X]o concentration of ion “X” outside of the cell
[X]i concentration of ion “X” inside of the cell

2. in the example above (see Figure 2.5B),

EK = 58 log [1]o = -58 mV

1 [10]i

4. thus, for every 10-fold change in the concentration gradient of K+, there will be a
change of 58 mV in the equilibrium potential for K+
5. consider the Study Questions below (end of handout)
B. Goldman equation
1. in a multi-ion environment, the concentration gradients of each ionic species
AND the relative permeabilities of the plasma membrane to each ion must be
considered to accurately predict the membrane potential

4
 Overview of Neural Signaling

2. fortunately, for most neurons, we only need to be concerned with three ions:
Na+, K+, and Cl- (see Table 2.1 for actual concentrations of these ions in
mammalian neurons)

V or Em = 58 log X (PK[K]o + PNa[Na]o + PCl[Cl]i)

(PK[K]i + PNa[Na]i + PCl[Cl]o)

V voltage across the plasma membrane (membrane potential)

P permeability of the plasma membrane to each ion

3. consider the model system in Figure 2.7A

a. if the membrane is permeable only to K+, then the membrane potential
will be –58 mV
b. if the membrane is permeable only to Na+, then the membrane
potential will be +58 mV
c. if the membrane is equally permeant to both K+ and Na+, then the
membrane potential will be 0 mV
4. now consider the changes in membrane permeability that underlie the neuronal
action potential (see Figure 2.7B)
a. at rest the neuronal membrane is permeable to K+, but not to Na+
(PK+>>PNa+); thus, the resting membrane potential approaches EK
b. for a very brief interval (about 1 msec), the membrane may become
highly permeable to Na+ (PK+<<PNa+); thus, at the peak of the action
potential, the membrane potential approaches ENa

IV. view an online animation that accompanies Neuroscience, 5th. Ed., Chapter 2: Animation 2.2
Electrochemical Equilibrium [click here]

STUDY QUESTIONS
Suppose that extracellular sodium is 10 times greater than intracellular sodium, and the neuronal
membrane is now selectively permeable only to sodium. What will be the resting membrane potential?

A. + 58 mV
B. +29 mv
C. -29 mV
D. -58 mV

5
 Overview of Neural Signaling

Now, suppose that extracellular calcium is 10 times greater than intracellular calcium, and the neuronal
membrane is now selectively permeable only to calcium. What will be the resting membrane potential?

A. + 58 mV
B. +29 mv
C. -29 mV
D. -58 mV

Next, suppose that the membrane is now permeable only to chloride ions and extracellular chloride is
10 times greater than intracellular chloride. What will be the resting membrane potential?

A. + 58 mV
B. +29 mv
C. -29 mV
D. -58 mV

Lastly, consider the situation for mainly neurons in the developing brain when intracellular chloride is
about 10 times greater than extracellular chloride. If the neuronal membrane is only permeable to
chloride ions, what will be the resting membrane potential?
A. + 58 mV
B. +29 mv
C. -29 mV
D. -58 mV

6
 Overview of Neural Signaling

Medical Neuroscience | Tutorial Notes

Ionic Basis of the Action Potential

MAP TO NEUROSCIENCE CORE CONCEPTS5

NCC2. Neurons communicate using both electrical and chemical signals.

LEARNING OBJECTIVES
After study of the assigned learning materials, the learner will:

1. Use the Goldman (and Nernst) equations to predict the membrane potential of neurons given
knowledge of the concentration gradients of ions and their relative permeabilities across the
neuronal plasma membrane.
2. Describe the ionic basis of the action potential in terms of the voltage- and time-dependant
changes in ionic permeabilities that occur across the neuronal plasma membrane.
3. Describe the driving force for current flow across the plasma membrane.
4. With careful precision, relate the time course of changes in Na+ and K+ conductance to changes
in membrane potential during the action potential.
5. Characterize the refractory period for action potential generation.

TUTORIAL OUTLINE

I. Introduction: changes in membrane permeability underlie the neuronal action potential

1. let’s review the changes in membrane permeability that, in principle, underlie the
neuronal action potential (see Figure 2.7B6)
1. at rest the neuronal membrane is permeable to K+, but not to Na+ (PK+>>PNa+);
thus, the resting membrane potential approaches EK
2. for a very brief interval (about 1 msec), the membrane may become highly
permeable to Na+ (PK+<<PNa+); thus, at the peak of the action potential, the
membrane potential approaches ENa

2. view an online animation that accompanies Neuroscience, 5th. Ed., Chapter 2: Animation
2.2 Electrochemical Equilibrium [click here]

II. Ionic currents across neuronal membranes

5
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7
 Overview of Neural Signaling

A. voltage clamp method (see Box 3A, p. 42)

1. necessary to study permeability changes without evoking action potentials
(because action potentials involve explosive changes in membrane potential, it
is difficult to control and study membrane permeability when they occur)
2. method of recording neural activity that allows experimenters to measure
current flow across a membrane without changing the membrane potential
B. membrane permeability is voltage dependent (see Figure 3.1)
1. depolarization of the membrane to near 0 mV induced two types of currents
that could be distinguished based on their direction of flow across the
membrane and their distinct time courses
a. transient inward current
b. delayed outward current
C. these currents are carried by Na+ and K+
1. based on the Nernst equation, Hodgkin and Huxley knew the equilibrium
potentials for Na+ and K+
2. remember, at an equilibrium potential, there is no net current flow (the
concentration gradient is exactly counterbalanced by the electrical gradient)
3. so, adjusting the membrane potential to the equilibrium potential of a given ion
should remove the contribution of that ion to the total current flowing across
the membrane (see Figures 3.2 & 3.3)
a. with increasing depolarization of the plasma membrane, both the
transient inward and delayed outward currents changed in magnitude
b. transient inward current
(1) depolarization to small positive potentials (e.g., +26 mV)
reduced the size of transient inward current
(2) at +52 mV (very near ENa for the experimental system) the
transient inward current disappeared
(3) at even more depolarizing potentials (+65 mV), the inward
current reversed
(4) the behavior of the inward current was nearly identical to what
was predicted for a Na+ current, given the known
concentrations of Na+ inside and outside of the axon
(5) the identity of this current was confirmed in ion-substitution
experiments where Na+ was removed from the extracellular
medium (see Figure 3.4)
c. delayed outward current
(1) as depolarization increased, the delayed outward current
steadily increased in magnitude

8
 Overview of Neural Signaling

(2) removal of Na+ from the extracellular medium did not affect the
delayed outward current
(3) this behavior is consistent with a K+ current, which further
experiments confirmed (see Figure 3.5)

III. Reconstruction of the action potential

A. effect of voltage on Na+ and K+ conductance
1. conductance: the reciprocal of membrane resistance; the electrical term used
to describe the opening and closing of ion channels (symbolized as g)
2. easily determined by rearranging Ohm’s law and substituting a “driving force”
term for voltage
I=gV
A “driving force” term can be substituted for V to account for the
difference between the membrane potential and Nernst equilibrium
potential for a given ion; thus
Iion = gion (Vm – Eion)
Iion Ionic current
gion Ionic conductance
Vm Membrane potential
Eion Nernst equilibrium potential

3. Hodgkin and Huxley recorded membrane currents under voltage clamp

conditions and calculated membrane conductance for Na+ and K+
a. both conductances are voltage-dependent (implies that the mechanism
responsible for conductance must be capable of sensing changes in
membrane potential)
b. both conductances change over time (see Figure 3.6)
i. after activation, the Na+ conductance inactivates, which means
the current stops flowing despite the persistence of an
electrochemical driving force
ii. not so for the K+ conductance; current flows as long as there is
an electrochemical driving force
B. The Hodgkin-Huxley model of the action potential (see Figures 3.8 & 3.9)
1. ACTION POTENTIAL IS EXPLAINED BY VOLTAGE-DEPENDENT AND TIME- DEPENDENT CHANGES IN
+ +
THE PERMEABILITY OF THE NEURONAL MEMBRANE TO Na AND K

2. this model also explains the threshold for the generation of an action potential
(see Box 3B) and the all-or-none (regenerative) character of the action potential
(see Figure 3.9)
3. model also explains the refractory period of the action potential

9
 Overview of Neural Signaling

a. when the Na+ conductance is inactive, it is not possible for the local
region of membrane to generate another action potential; this period of
Na+ inactivation is called the absolute refractory period
b. after Na+ de-inactivation (removal of Na+ inactivation), it is possible to
generate an action potential, but the prolonged activation of the K+
conductance means that it will be more difficult to elicit another action
potential; this period of K+ conductance activation after Na+ de-
inactivation is termed the relative refractory period
4. Hodgkin-Huxley model holds for the vast majority of neurons in the CNS
3. Review the content of this tutorial by viewing an online animation that accompanies
Neuroscience, 5th. Ed., Chapter 2: Animation 2.3 The Action Potential [click here]

STUDY QUESTION
The regenerative nature of the action potential is explained by a fast positive cycle turning at a faster
rate than a slower, negative cycle. Given these facts, why is the action potential a “spike”? That is, what
single factor best explains the short duration of the typical, neuronal action potential?
A. Depletion of extracellular sodium.
B. Depletion of intracellular potassium.
C. Potassium channel inactivation.
D. Sodium channel inactivation.

10
 Overview of Neural Signaling

Medical Neuroscience | Tutorial Notes

Molecular Mechanisms of Action Potential Generation

MAP TO NEUROSCIENCE CORE CONCEPTS7

NCC2. Neurons communicate using both electrical and chemical signals.

LEARNING OBJECTIVES
After study of the assigned learning materials, the learner will:

6. Describe the molecular properties of sodium and potassium channels that explain the voltage-
and time-dependent permeability changes underlying action potential generation.
7. Describe the molecular mechanisms for establishing chemical gradients for sodium and
potassium across the neuronal plasma membrane.

TUTORIAL OUTLINE

I. Introduction: review the Hodgkin-Huxley model of the action potential (see Figures 3.8 & 3.98)
4. THE ACTION POTENTIAL IS EXPLAINED BY VOLTAGE-DEPENDENT AND TIME- DEPENDENT CHANGES IN THE
+ +
PERMEABILITY OF THE NEURONAL MEMBRANE TO Na AND K

5. this model explains the threshold for the generation of an action potential (see Box 3B)
and the all-or-none (regenerative) character of the action potential (see Figure 3.9)
6. review the ionic basis of the action potential by viewing an online animation that
accompanies Neuroscience, 5th. Ed., Chapter 2: Animation 2.3 The Action Potential
[click here]

II. Functional and molecular models of Na+ and K+ channels

A. functional model (see Figure 4.3)
1. Na+ channels: Closed ⇔ open ⇔ inactivated ⇔ closed
2. K+ channels: Closed ⇔ open ⇔ closed
B. molecular model (see Figures 4.6 & 4.8)
a. integral membrane proteins
(i) a series of membrane-spanning domains

7
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11
 Overview of Neural Signaling

i. “pore loop” that forms the channel for the selective passage of a
certain ionic species
ii. “voltage-sensor” comprised of a segment of positively charged
amino acid residues in an helical structure that changes its
conformation in response to changes in membrane potential (see
Figure 4.8)
iii. segment that allows for the aggregation of subunits (or the folding
of a single subunit) into a functional three-dimensional channel
structure
(ii) extracellular domain
i. may include a segment that binds certain toxins
(iii) intracellular domain
i. may include a segment of amino acids that “plugs” the pore during
sustained depolarization (inactivation)
C. some channels are comprised of a single protein sequence (Na+), others require the
aggregation of multiple subunits (K+)
D. CLINICAL APPLICATION: several skeletal and cardiac muscle disorders appear to be the
consequences of faulty ion channels, produced by mutations in the genes that encode
channel proteins (see Box 4D)

IV. Ion pumps

A. pumps, exchangers and transporters establish concentration gradients that are
discharged when ions flow through channels (see Figure 4.9)
B. Na+/K+ ATPase
1. experiments demonstrated that Na+ efflux is linked to K+ influx and the supply of
intracellular ATP (see Figure 4.10A)
2. stoichiometry of ionic fluxes
+
a. THREE Na ions are transported out of cell for every TWO K+ ions
transported into cell
b. therefore, the pump is electrogenic: since there is a net loss of one
positive charge for each cycle, pump activity can hyperpolarize the
plasma membrane
3. model of pump activity (see Figure 4.10B)
a. integral membrane protein
b. intracellular domain with sites for ATP binding and hydrolysis
c. phosphorylation/dephosphorylation cycle of the pump induces a series
of conformational changes that allow for the translocation of Na+ and K+
across the plasma membrane

12
 Overview of Neural Signaling

d. view an online animation that accompanies Neuroscience, 5th. Ed.,

Chapter 4: Animation 4.2 the Sodium-Potassium Pump [click here]
C. there are other important pumps and ion exchangers for maintenance of Ca++, Cl- and H+
homeostasis (see Figure 4.9)

13
 Overview of Neural Signaling

Medical Neuroscience | Tutorial Notes

Propagation of Action Potentials

MAP TO NEUROSCIENCE CORE CONCEPTS9

NCC2. Neurons communicate using both electrical and chemical signals.

LEARNING OBJECTIVES
After study of the assigned learning materials, the learner will:

8. Describe the ionic basis of the action potential in terms of the voltage- and time-dependent
changes in ionic permeabilities that occur across the neuronal plasma membrane.
9. Characterize the advantages of myelination for the conduction of an action potential along an
axon.

TUTORIAL OUTLINE

I. Introduction

7. let’s review the changes in membrane permeability that, in principle, underlie the
neuronal action potential by viewing again a short online animation that accompanies
Neuroscience, 5th. Ed., Chapter 2: Animation 2.3 The Action Potential [click here]

II. Propagation of action potentials

A. leakiness of axonal membranes prevents the effective conduction of subthreshold
depolarizing potentials for more than just a very short distance (< 1 mm) (remember,
that neurons – and their axons – are poor conductors of electricity) (see Figure 2.310)
B. the action potential provides a means of overcoming the inherent leakiness of the
axonal membrane (see Figures 3.10–3.12)
1. action potential propagation requires the coordinated action of two forms of
current flow:
a. passive flow of current down the axon
b. active flow of current through voltage-dependent membrane channels

9
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14
 Overview of Neural Signaling

2. because resistance is inversely related to diameter, larger axons present less

resistance to passive current flow and the “conduction” (speed of transmission)
of electrical signals is faster in larger diameter axons
3. CONDUCTION VELOCITY IS DIRECTLY PROPORTIONAL TO AXONAL DIAMETER

C. as action potentials propagate along an axon, recently excited membrane becomes

refractory for some brief period of time
1. Na+ channels remain inactivated (absolute refractory period)
2. K+ channels are activated (relative refractory period)
D. myelination increases the speed of action potential propagation (see Figure 3.12)
1. myelination increases the efficiency of passive current flow down an axon by
reducing the inherent leakiness of the axonal membrane with the addition of
insulating glial membranes
2. Na+ channels are concentrated at the Nodes of Ranvier
3. saltatory conduction; action potentials “jump” from one node to the next
4. consequently, loss of myelination, such as occurs in demyelinating diseases like
multiple sclerosis, severely slows and might even impede the propagation of
action potentials along axons
E. view Animation 3.2 - Impulse Conduction in Axons [click here]

STUDY QUESTION
One of the neurological diseases that can severely impair neurologic function is multiple sclerosis.
Thankfully, for many patients who live with this disorder, there are interventions that may modify the
progression of disease and bring relief for managing daily symptoms. Multiple sclerosis involves an
immunological attach against the brain cells that make myelin. Knowing this, what do you think would
be the underlying neurobiological insults that led to impairment of neurological function?

A. breakdown of the blood-brain barrier

B. insufficient clearance of neurotransmitters upon release from presynaptic terminals
C. failure of action potential propagation
D. all of the above

15
 Overview of Neural Signaling

Medical Neuroscience | Tutorial Notes

Synaptic Transmission

MAP TO NEUROSCIENCE CORE CONCEPTS11

NCC2. Neurons communicate using both electrical and chemical signals.

LEARNING OBJECTIVES
After study of the assigned learning materials, the learner will:

1. Compare and contrast the structural and functional similarities and differences between
electrical and chemical synapses.
2. Describe the sequence of events responsible for the transmission of a neural impulse from one
neuron to the next via a chemical synapse.
3. Characterize the critical role of calcium in chemical neurotransmission.
4. Discuss the mechanisms of action by which Botox affects neurotransmission.

TUTORIAL OUTLINE

I. Introduction
A. Two types of synapses:
1. electrical synapses (gap junctions): permits passive current flow through open
pores that interconnect adjacent neurons
2. chemical synapses: enable intercellular communication via the secretion of
chemical messengers that must diffuse the gap between adjacent neurons
II. General comparison of electrical and chemical synapses (summarized in Table at end of
handout; also see Figure 5.112)
III. A closer look at chemical synapses (see Figure 5.3)
A. sequence of events involved in chemical neurotransmission
[note: the numbered items below correspond to the numbers in Figure 5.3]
1. the presynaptic terminal contains:
a. neurotransmitter that is synthesized and stored in synaptic vesicles
b. a pool of vesicles that are “docked” along an active zone in the
presynaptic membrane, poised to fuse with the plasma membrane
11
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16
 Overview of Neural Signaling

2. an action potential invades the presynaptic terminal

3. associated change in membrane potential causes the opening of voltage-gated
Ca++ channels
4. because of the steep concentration gradient for Ca++ across the plasma
membrane, Ca++ rushes into the presynaptic terminal
5. via a cascade of molecular events, Ca++ causes the fusion of “docked” vesicles
with the presynaptic plasma membrane along the synaptic cleft
6. vesicle fusion releases neurotransmitter into the synaptic cleft
7. neurotransmitter diffuses across the synaptic cleft and binds specific receptors
in the post synaptic membrane
8. binding of neurotransmitter causes the opening or closing of ion channels in the
postsynaptic membrane
9. current flows through open channels in the postsynaptic membrane or that
membrane becomes less “leaky” due to closure of certain channels;
consequently, the postsynaptic membrane becomes either depolarized or
hyperpolarized
a. if positive current flows (i.e., cations in) and the membrane is
depolarized, voltage-gated Na+ channels will open and a postsynaptic
potential will be generated; if threshold is reached, the postsynaptic
neuron will then fire an action potential
b. if negative current flows (i.e., anions in or cations out), then the
membrane will be hyperpolarized and the postsynaptic membrane will
be further from threshold and less likely to fire an action potential
c. meanwhile, neurotransmitter is removed by glial or presynaptic uptake,
or by enzymatic degradation
10. vesicular membrane is retrieved from presynaptic membrane (see Figure 5.9)
B. critical role of calcium in vesicle fusion
1. depolarization of the presynaptic membrane opens voltage-gated Ca++ channels
(see Figure 5.10)
2. influx of Ca++ is both necessary and sufficient for vesicle fusion and
neurotransmitter release (see Figure 5.11)
a. fusion requires the coordinated interactions of dozens of molecules in
the vesicular membrane, presynaptic cytosol and presynaptic terminal
membrane (see Figure 5.13)
b. influx of Ca++ is the trigger that orchestrates these interactions, by
binding first to a vesicular membrane protein, synaptotagmin
c. a complex of proteins (SNARE complex) are then activated to
accomplish the fusion of docked vesicles (see Figure 5.14A, B)
d. other proteins (see Figure 5.13) are involved in:

17
 Overview of Neural Signaling

(i) the “docking” and “priming” process

(ii) the formation of a “fusion pore”
(iii) the incorporation of vesicular membrane into presynaptic
terminal membrane
(iv) the recycling of vesicular membrane (see Figure 5.15)
e. several of these proteins are the targets of natural toxins produced by
certain bacteria, plants and animals (see Boxes 5B & 5C)
(i) clostridial toxins produced by certain types of bacteria are
responsible for diseases, such as botulism and tetanus
(ii) many toxins are proteases that disrupt the SNARE complex
- some cleave the synaptic vesicle protein, synaptobrevin
- others cleave syntaxin or SNAP-25
(iii) cleavage of important synaptic vesicle proteins renders the
synapse incapable of vesicle fusion and therefore, incapable of
neurotransmission
(iv) Clinical application: “Botox” is a commercial formulation of the
botulinum toxin that is especially useful clinically to treat
spasticity and other forms of involuntary muscle fasciculation
and twitching
C. let’s summarize the processes by which chemical synapses operate by viewing a short
online animation that accompanies Neuroscience, 5th. Ed., Chapter 5: Animation 5.1
Synaptic Transmission [click here]

STUDY QUESTION
The SNARE complex forms as proteins bound to the vesicle membrane interact with proteins bound to
the presynaptic terminal. What is the function of the SNARE complex?
A. The SNARE complex facilitate the formation of a fusion pore between the vesicle membrane and
the presynaptic terminal membrane.
B. The SNARE complex functions to snare free neurotransmitter that diffuses into the synaptic
cleft.
C. The SNARE complex functions to facilitate the retrieval of vesicle membrane from the
presynaptic membrane after release of neurotransmitter.
D. The SNARE complex functions to facilitate the loading of presynaptic vesicles with
neurotransmitter.
E. The SNARE complex functions to snare recycled vesicles and deliver them to endosomes in the
presynaptic terminal.

18
 Overview of Neural Signaling

Table. Summary of electrical and chemical synapses in the CNS.

Electrical Synapses Chemical Synapses

General function

Very rapid communication or synchronization of a small Major means of communication between neurons;
pool of nearby neurons provides basis of neural plasticity

Allows for passage of small, non-current carrying Molecules do not pass from the cytoplasm of one cell to
molecules (e.g., ATP, second messengers) another

Prevalence

Abundant in developing nervous system Rare and/or very immature in developing nervous system

Relatively rare in mature nervous system Principal type of synapse in mature nervous system

Morphology

Plasma membranes of communicating cells are closely Plasma membranes are close, but separated by a distinct
apposed synaptic cleft

Formed by the alignment of connexons, also called gap Synaptic cleft; no connexons
junctions, which are made from integral membrane
proteins in both plasma membranes that form channels
for the passage of small molecules (see Figure 5.2)

No synaptic vesicles or neurotransmitter molecules Synaptic vesicles contain neurotransmitter molecules

No post synaptic receptors Neurotransmitter-specific receptors (i.e., ligand-gated

receptors) in post synaptic plasma membrane

Usually occur between neuronal cell bodies (somatic) or May be axo-dendritic, axo-somatic, axo-axonal (and
dendrites (dendro-dendritic) dendro-dendritic)

Physiology

Current flows by direct diffusion of ions from one cell to Current does not flow directly from one cell to another;
another; also other important small molecules (e.g., ATP, post synaptic current develops secondarily to binding of
++
cAMP, Ca ) may pass neurotransmitter to its receptor and the opening/closing
of channels

Very rapid communication; synaptic delay < 0.1 msec Rapid communication, but slower than electrical
synapses; synaptic delay ~ 0.5 msec

Communication may be bi-directional Communication is only uni-directional

Probability of transmission (= presynaptic action Probability of transmission is more variable (~20-90%)

potential followed by postsynaptic potential) is very high
(~100%)

19
 Overview of Neural Signaling

Medical Neuroscience | Tutorial Notes

Neurotransmitters

MAP TO NEUROSCIENCE CORE CONCEPTS13

NCC2. Neurons communicate using both electrical and chemical signals.

LEARNING OBJECTIVES
After study of the assigned learning materials, the learner will:

5. Name the major small molecule neurotransmitters and neuropeptides in the CNS and briefly
state the function of each.
6. Account for the factors that determine the effect of neurotransmitters on postsynaptic neurons.

TUTORIAL OUTLINE

IV. Overview of neurotransmitters

B. review mechanisms of chemical synaptic neurotransmission (see Figure 5.314)
C. two broad classes based on molecular size and chemical class (see Figure 6.1)
1. small-molecule neurotransmitters
a. typically mediate rapid synaptic effects (i.e., post synaptic potentials
are relatively brief, a few msec) when bound to ionotropic receptors
b. however, they may elicit long-lasting effects when bound to
metabotropic receptors – see below
c. most important representatives
(i) glutamate: major excitatory neurotransmitter in the CNS
- review the organization of glutamatergic synapses
by viewing a short online animation that
accompanies Neuroscience, 5th. Ed., Chapter 6:
Animation 6.2 Neurotransmitter Pathways:
Glutamate [click here]
(ii) GABA: major inhibitory neurotransmitter in the brain
(iii) glycine: major inhibitory neurotransmitter in the spinal cord

13
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20
 Overview of Neural Signaling

(iv) acetylcholine: excitatory neurotransmitter of somatic motor

neurons, major excitatory neurotransmitter in autonomic
ganglia and post ganglionic parasympathetic fibers, and special
modulatory systems in the CNS
- for an overview of a central cholinergic synapse, see
Figure 6.2
- review the organization of cholinergic synapses by
viewing Animation 6.1 Neurotransmitter Pathways:
Acetylcholine [click here]
(v) biogenic amines (dopamine, serotonin): involved in motivation
and reward systems; also linked to several neuropsychiatric
disorders and movement disorders (see Boxes 6B & 6E and
Figures 6.11 & 6.13)
review the organization of dopaminergic synapses
by viewing Animation 6.3 Neurotransmitter
Pathways: Dopamine [click here]
- review the organization of serotonergic synapses by
viewing Animation 6.5 Neurotransmitter Pathways:
Serotonin [click here]
2. neuropeptides
a. mediate slower and more long-lasting synaptic effects (i.e., post
synaptic potentials may last 100s of msec to seconds, or even minutes
and longer) when bound to metabotropic receptors
b. most important
(i) substance P: a neurotransmitter of pain and temperature fibers
that synapse in the spinal cord
(ii) opioids: have analgesic effects in brain; also inhibit release of
substance P in spinal cord
(iii) hypothalamic releasing hormones (affect secretory cells in
anterior pituitary) & posterior pituitary hormones
3. “unconventional” (i.e., poorly understood) neurotransmitters
a. ATP and other purines
(i) ATP may be co-released with other small molecule
neurotransmitters
(ii) Once in extracellular spaces, ATP is metabolized into adenosine,
which has its own biogeneic activity
(iii) Adenosine is now thought to be an important signal (in the
hypothalamus, at least) that modulates wakefulness by
promoting sleepiness

21
 Overview of Neural Signaling

(iv) Xanthines (including caffeine) block adenosine receptors (which

is why caffeine fights sleepiness!)
b. Endocannabinoids
(i) produced from membrane lipids and bind to receptors that also
bind the psychoactive component of marijuana
(ii) hydrophobic; hence, they readily diffuse through neuronal
membranes and leave neurons where they can interact with
membrane bound receptors on other cells
(iii) play a role in the plasticity of inhibitory circuits in the brain (see
Figure 6.19)
c. Nitric oxide (NO)
(i) Gas produced from the metabolism of the amino acid, arginine
– a process regulated by calcium
(ii) Since it is a gas, if can diffuse freely across neuronal and glial cell
membranes to influence a local volume of brain tissue
(iii) Some actions of NO are mediated by the activation of an
enzyme guanylyl cyclase, which when activated produces the
second messenger, cGMP (see Figure 6.20)
(iv) a passing note of interest … Viagra and related drugs work by
affecting NO-mediated signaling

V. Neurotransmitter cycle for small-molecule neurotransmitters and neuropeptides (see Table

below and Figure 5.5; see also Figure 6.5 for glutamate cycle)

Small-molecule Neuropeptides
neurotransmitters
Synthesis in presynaptic terminal by in cell bodies in the form of pre-
specific enzymes (pro)-peptide and later cleaved
into active transmitter
Packaging & release small vesicles near active zone in large vesicles away from active
presynaptic terminal zone
low frequency of neural activity high frequency of neural activity
sufficient for release are required for release
docked vesicles released with vesicles only released with influx
influx of even low levels of Ca++ of high levels of Ca++
rapid onset slower onset
Removal of neurotransmitter passive diffusion passive diffusion
reuptake into presynaptic --
terminal
uptake into astrocytes --
enzymatic degradation enzymatic degradation

22
 Overview of Neural Signaling

VI. Activities of neurotransmitters

A. the actions of a neurotransmitter is NOT dictated by the chemical structure of the
neurotransmitter
B. the response elicited by any given neurotransmitter will depend upon the post synaptic
receptor and the associated types of channels and second messenger systems (more on
this topic in the next tutorial)

STUDY QUESTIONS
Q1. Which of the following substances is associated with fast, excitatory neurotransmission in the
central nervous system?
A. dopamine
B. acetylcholine
C. gamma aminobutyric acid
D. endorphin
E. glutamate

Q2. Which of the following substances plays a role in the plasticity of inhibitory circuits in the brain?
A. gamma aminobutyric acid
B. endocannabinoids
C. adenosine
D. nitric oxide
E. dopamine

23
 Overview of Neural Signaling

Medical Neuroscience | Tutorial Notes

Neurotransmitter Receptors

MAP TO NEUROSCIENCE CORE CONCEPTS15

NCC2. Neurons communicate using both electrical and chemical signals.

LEARNING OBJECTIVES
After study of the assigned learning materials, the learner will:

7. Discuss the means by which ligand-gated ion channels affect the membrane potential of
postsynaptic neurons.
8. Compare and contrast the structure and function of ligand-gated ion channels and metabotropic
(G-protein coupled) receptors.
9. Discuss the properties of the NMDA receptor for glutamate and why it is important for synaptic
plasticity.
10. Account for the factors that determine the effect of neurotransmitters on postsynaptic neurons.

TUTORIAL OUTLINE

VII. Overview of neurotransmitters

D. review mechanisms of chemical synaptic neurotransmission (see Figure 5.316)
E. two broad classes based on molecular size and chemical class (see Figure 6.1)

VIII. Ionotropic receptor (ligand-gated ion channel) activation

A. overview
1. the same molecular complex binds the neurotransmitter and forms a channel
for the passage of ions across the plasma membrane (see Figure 5.16A)
2. mediate most rapid post synaptic effects (typically, in millisecond range)
3. remember, the response elicited by any given neurotransmitter will depend
upon the postsynaptic receptor and the associated types of channels and second
messenger systems that may be activated

B. general molecular structure (see Figure 6.3A)

1. comprised of four or five subunits

15
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24
 Overview of Neural Signaling

2. each subunit has

a. extracellular N-terminal domain that contains the neurotransmitter
receptor
b. membrane spanning domain that forms the ion channel
c. intracellular domain, where other molecules may interact to modulate
channel function
3. different subunits may be combined to produce functional diversity for any
given type of channel (see Figure 6.3F)
C. important examples include:
1. nicotinic acetylcholine receptors (see Figures 6.3)
2. AMPA & NMDA receptors for glutamate (see Figures 6.6 & 6.7)
3. GABAA receptors (see Figures 6.9)
D. postsynaptic currents induced by ligand binding to ionotropic receptors
1. channels are gated by binding of neurotransmitter to receptor site (in contrast
to voltage-gated ion channels)
2. net current flows through channel pores if:
a. channel conductance (g) > 0, which happens rapidly when
neurotransmitters bind
b. there is a driving force for current flow; or in mathematical terms, when
Vm-Erev ≠ 0 (the driving force can be positive or negative)
3. Ohm’s law for ligand-gated ion channels:

PSC = gligand (Vm-Erev)

PSCpostsynaptic current induced by ligand binding

gligand conductance gated by ligand binding
Vm membrane potential when ligand binds
Erevreversal potential of the ligand-gated conductance
4. consider the nicotinic acetylcholine receptor at the neuromuscular junction (see
Figure 5.17 & 6.3)
a. the channel is gated by the binding of acetylcholine released by the
terminals of motor neurons in the brainstem and spinal cord
b. the channel pore is relatively non-selective (much less selective than
typical voltage-gated ion channels); most univalent cations can pass
(e.g., sodium, potassium)
c. in most muscle fibers, Erev is near 0 mV
d. postsynaptic current, called the endplate current (EPC), is a product of
conductance (binding of acetylcholine) and driving force (membrane
potential relative to the reversal potential)

25
 Overview of Neural Signaling

e. consider the Study Questions at the end of these tutorial notes

E. consider the behavior of an unusual, but critically important ligand-gated ion channel
for glutamate: the NMDA receptor (see Figure 6.6)
1. channel pore is gated by the binding of glutamate, but also requires the
presence of a “co-agonist”, the amino acid glycine
2. channel pore contains a binding site for magnesium (Mg++)
a. when the postsynaptic neuron is at resting membrane potentials,
extracellular Mg++ is attracted to the channel pore (by electrostatic
forces) and effectively blocks the pore
b. when the postsynaptic neuron is depolarized, extracellular Mg++ is
repelled from the channel pore (again, by electrostatic forces) and the
pore is unblocked
c. thus, the channel is gated by glutamate, but the conductance is voltage-
dependent
3. channel pore is relatively non-selective for cations (Na+, K+, Ca++)
a. the entrance of is Ca++ significant, since Ca++ is a key second-messenger
within the cytoplasm mediating a variety of effects that can impact the
structure and function of postsynaptic neurons
b. the amount of Ca++ that enters a postsynaptic process when NMDA
receptors are activated and the postsynaptic neuron is depolarized is a
critical factor in synaptic plasticity (much more on this in Friday’s
session)

III. Metabotropic receptors

A. termed metabotropic, because the eventual passage of ions through a channel requires
one or more metabolic steps (see Figure 5.16B & 6.4)
1. receptor and ion channel are separate molecules in the membrane
2. receptor interacts with the ion channel indirectly via the activity of a set of G-
proteins (thus, called “G-protein-coupled receptors”)
3. typically, energized G-proteins in turn activate an effector enzyme, which
produces a second messenger (see Figures 7.5 & 7.6)
a. effector enzymes produce a variety of second messenger systems each
of which may have distinct effects
b. by this means, the triggering molecular signal (i.e., a neurotransmitter)
is greatly amplified (one signal ⇒ many second messengers) and
diversified (one signal ⇒ many intracellular effects) (see Figure 7.2)
4. mediate slower developing and more persistent post synaptic effects than the
ionotropic receptors
a. onset of post synaptic potential within a few to 10s of milliseconds of
the presynaptic action potential

26
 Overview of Neural Signaling

b. post synaptic potential may last for 100s of milliseconds or longer

c. certain second messenger systems may affect gene transcription and
thereby produce post synaptic effects that last many days (see Figure
7.11)
B. general molecular structure
1. receptor molecule is a monomeric protein (see Figure 6.4A)
a. extracellular domain, including the N-terminus
b. seven membrane spanning domains that form the binding site for the
neurotransmitter (common to all G-protein-coupled integral membrane
proteins)
i. stay tuned! this family of G-protein coupled proteins show up
in surprising places (besides postsynaptic membranes):
- the detection of odors is based upon the activity of one
member of this family of proteins
- another member of this family mediates the conversion of
photons into electrical signals in photoreceptors
ii. intracellular domain, which contains portions of the C-terminus
and membrane spanning domains that bind the G -proteins
C. important examples of metabotropic receptors include: muscarinic acetylcholine
receptors, metabotropic glutamate receptors, and α & β adrenergic receptors

IV. remember, the response elicited by any given neurotransmitter will depend upon the post
synaptic receptor and the associated types of channels and second messenger systems

STUDY QUESTIONS
1. What is the EPC when acetylcholine binds and the muscle fiber is clamped at -100 mV?
(remember that an inward current is carried by positive charge flowing into the cell)
A. large inward current
B. small inward current
C. no net current
D. small outward current
E. large outward current

2. What is the EPC when acetylcholine binds and the muscle fiber is clamped at -20 mV?
A. large inward current
B. small inward current
C. no net current
D. small outward current
E. large outward current

27
 Overview of Neural Signaling

3. What is the EPC when acetylcholine binds and the muscle fiber is clamped at 0 mV?
A. large inward current
B. small inward current
C. no net current
D. small outward current
E. large outward current

4. What is the EPC when acetylcholine binds and the muscle fiber is clamped at +20 mV?
A. large inward current
B. small inward current
C. no net current
D. small outward current
E. large outward current

5. What is the EPC when acetylcholine binds and the muscle fiber is clamped at +70 mV?
A. large inward current
B. small inward current
C. no net current
D. small outward current
E. large outward current

one final question to consider:

6. What explains the value of Erev at the motor endplate?
A. Erev is the membrane potential that drives Na+ into the cell, but precisely opposes the
outflow of K+
B. Erev is the membrane potential that drives K+ out of the cell, but precisely opposes the influx
of Na+
C. Erev is the membrane potential at which there is no net flow of current

28
 Overview of Neural Signaling

Medical Neuroscience | Tutorial Notes

Synaptic Integration

MAP TO NEUROSCIENCE CORE CONCEPTS17

NCC2. Neurons communicate using both electrical and chemical signals.

LEARNING OBJECTIVES
After study of the assigned learning materials, the learner will:

11. Discuss the concepts, “excitatory postsynaptic potential” (EPSP) and “inhibitory postsynaptic
potential” (IPSP), defining them in terms of the reversal potential for the postsynaptic current
and the threshold for generating an action potential.
12. Describe how postsynaptic potentials can summate in space and time.

TUTORIAL OUTLINE

IX. Overview of neurotransmitters

F. review mechanisms of chemical synaptic neurotransmission (see Figure 5.318)
G. two broad classes based on molecular size and chemical class (see Figure 6.1)

X. Excitatory and inhibitory post synaptic potentials (PSPs) (see Figure 5.21)
A. excitatory post synaptic potentials (EPSPs)
1. postsynaptic potential that increases the probability that the postsynaptic
neuron will generate an action potential
2. Erev for the ligand-gated conductance is above than threshold for firing an action
potential
B. inhibitory post synaptic potentials (IPSPs)
1. post synaptic potential decreases the probability that the post synaptic cell will
generate an action potential
2. Erev for the ligand-gated conductance is below the threshold for firing an action
potential
C. can the same neurotransmitter induce EPSPs and IPSPs? … YES!

17
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Figure references to Purves et al., Neuroscience, 5 Ed., Sinauer Assoc., Inc., 2012. [click here]

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 Overview of Neural Signaling

1. whether a neurotransmitter is excitatory or inhibitory is determined by its

reversal potential relative to threshold
2. Erev is determined by the concentration gradient(s) of the permeant ion(s)
3. a change in concentration gradient(s) could shift Erev to one side of threshold or
the other
4. for some neurons at least, this happens in development as chloride pumps
mature and intracellular chloride concentration falls
a. thus, GABA is excitatory for many immature neurons in the brain
because Cl- concentration is high inside cells and low outside cells
b. but, GABA is inhibitory for most if not all mature neurons because
chloride pumps develop that reverse the gradient: Cl- concentration
becomes low inside of cells and high in extracellular spaces (see Box
6D)

XI. Summation of post synaptic potentials (see Figure 5.22)

A. most synapses in the CNS produce very small post synaptic potentials (i.e., most EPSPs
are a millivolt or less—obviously, not sufficient to depolarize the neuronal membrane to
threshold for firing action potentials)
B. there are consequences of this fact:
1. the amplitude of postsynaptic depolarization is not what makes this potential an
EPSP (see above)
2. the small size of most EPSPs means that there is ample room for strengthening
(most synapses are far from their “ceiling” in terms of EPSP amplitude)
3. the small size of most EPSPs also means that should a synapse undergo
weakening, it may become “silent” or may physically disappear
4. with very few exceptions (Purkinje neurons in the cerebellum, and some types
of auditory neurons in the brainstem, being among the few), neurons in the CNS
must summate excitatory input from many sources in order to achieve
threshold and fire action potentials
C. because most neurons are innervated by 1000s of synapses, postsynaptic potentials
from many synapses do indeed summate in space (e.g., on the same dendrite) and time
(i.e., before concurrent PSPs decay)
D. whether the integrated sum of synaptic input causes a postsynaptic neurons to fire an
action potential at any moment in time depends upon:
1. the number and strength of EPSPs converging on the neurons dendritic arbor
(most excitatory inputs synapse on small protuberances emanating from
dendrites called, “dendritic spines”)
2. the number and strength of IPSPs converging on the neurons dendritic arbor
and soma (most inhibitory inputs synapse on dendritic shafts and cell bodies,
also called “somata”)

30
 Overview of Neural Signaling

STUDY QUESTION
Which of the following statements about excitatory postsynaptic potentials (EPSPs) in the central
nervous system (CNS) is most accurate?
A. Multiple EPSPs arriving together at different locations on the dendritic tree will cancel each
other out and the neuron will remain at rest.
B. By definition, the reversal potential of an EPSP is at or below the resting membrane potential.
C. The EPSPs in the central nervous system are much larger and much more likely to induce a
postsynaptic action potential, as compared to endplate potentials at neuromuscular junctions.
D. Multiple EPSPs occurring very close together in time can summate and help bring a neuron to
firing threshold.
E. EPSPs in the mature CNS are typically associated with GABAergic neurotransmission.

31
 Overview of Neural Signaling

Medical Neuroscience | Tutorial Notes

Synaptic Plasticity: LTP & LTD

MAP TO NEUROSCIENCE CORE CONCEPTS19

NCC2. Neurons communicate using both electrical and chemical signals.
NCC4. Life experiences change the nervous system.
NCC8. Fundamental discoveries promote healthy living and treatment of disease.

LEARNING OBJECTIVES
After study of today’s tutorial, the learner will:
1. Characterize general cellular mechanisms for synaptic change.
2. Characterize long-term potentiation (LTP).
3. Discuss the role of AMPA and NMDA subtypes of glutamate receptors in the induction and
maintenance of LTP.
4. Characterize long-term depression (LTD).
5. Discuss the molecular basis of LTD in the cerebral cortex and cerebellar cortex.

TUTORIAL OUTLINE

I. Introduction
A. plasticity: the capacity of the nervous system to change
B. plasticity occurs at all levels of organization (i.e., synapses, neural circuits, neural
systems)
C. plasticity is the basis of all neural functions that involve change (e.g., memory,
acquisition of motor skill or cognitive skills, adaptation to and recovery from injury or
disability)

II. Overview of long-term synaptic plasticity

A. changes in synaptic function that occur over a very long time frame: hours, days,
months (and maybe years)
B. changes in synaptic function are the cellular correlates of learning and memory
C. general cellular mechanisms for synaptic change:

19
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32
 Overview of Neural Signaling

1. neural activity triggers the activation of postsynaptic, second messenger

systems
2. the trigger is usually a specific alteration in the levels of intracellular calcium in
the postsynaptic neuron
3. Ca-dependent second messenger systems alter the activity of protein kinases
(phosphorylate target proteins) and phosphatases (dephosphorylate target
proteins)
4. alterations in protein phosphorylation mediate the early stages of long-term
synaptic plasticity (changes in phosphorylation induce changes in protein
function)
5. the more long-lasting changes in synaptic strength are brought about by
alterations in gene transcription induced by second messenger systems

III. long-term potentiation (LTP)

A. a long lasting INCREASE in postsynaptic currents induced by brief, high-frequency
stimulation of an afferent pathway (see Figure 8.720)
B. characteristics
1. the postsynaptic neuron must depolarize
a. induction of LTP requires pairing of presynaptic activity AND
postsynaptic depolarization (satisfies Hebb’s postulate)
b. mediated by NMDA receptors (see below)
2. LTP only occurs at active synapses (see Figures 8.7-8.9)
3. other inputs that are concurrently active, even weakly active, may
become potentiated (see Figure 8.9)
a. this allows for the selective enhancement of two distinct inputs
onto the same postsynaptic neuron
b. provides for the basis of associative learning (classical
conditioning)
4. persists for at least many weeks
5. studied primarily in the hippocampus, but basic phenomenon is
assumed to occur throughout the cerebral cortex (and subcortical
circuits)
C. molecular basis of LTP
1. induction of LTP requires activation of NMDA (N-methyl-D-aspartate)
subtype of ionotropic glutamate receptor
a. blockade of NMDA receptors has little effect on synaptic
responses elicited by low-frequency stimulation of an afferent
pathway

20 th
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33
 Overview of Neural Signaling

b. however, blockade of NMDA receptors prevents the

development of LTP during high-frequency stimulation
2. two factors explain the necessity of NMDA receptors for the induction
of LTP (see Figure 8.10):
a. voltage-dependency of NMDA receptor mediated currents
i. near resting membrane potentials, the channel pore is
blocked by magnesium ions (Mg++)
ii. with significant depolarization, Mg++ is expelled from the
channel pore and current is allowed to pass
b. permeability of NMDA channels to calcium
i. influx of calcium triggers a series of second messenger
systems that mediate the maintenance of LTP, especially
calcium-dependent protein kinases (see Figure 8.13)
ii. changes in the postsynaptic neuron involve the addition of
new ionotropic glutamate receptors (AMPA receptors) that
enhance the postsynaptic response
iii. such changes may “awaken” “silent synapses” (see Box 8B)
iv. in addition, new spine structures on dendrites (sites of
postsynaptic contact) may form (see Figure 8.12 & 8.15)
v. changes may also involve the presynaptic terminal (e.g.,
increased probability of exocytosis or increased amount of
glutamate released per vesicle)
3. Review the contributions of AMPA and NMDA receptors to LTP by viewing an
online animation that accompanies Neuroscience, 5th. Ed., Chapter 8:
Animation 8.2 AMPA and NMDA Receptors [click here]
4. consider the study question at the end of this tutorial

IV. long-term depression (LTD)

A. a long lasting DECREASE in postsynaptic currents induced by relatively prolonged,
low-frequency stimulation of an afferent pathway
B. LTD in the cortex (see Figure 8.16)
1. characteristics
a. induction of LTD requires pairing of presynaptic activity and
postsynaptic depolarization
b. phenomenon persists for at least many weeks
2. molecular basis of LTD
a. induction of LTD requires activation of NMDA receptors and
entrance of calcium into postsynaptic neuron
b. LTD in cortical neurons is induced when calcium levels are low

34
 Overview of Neural Signaling

i. remember, a large influx of calcium triggers LTP …

ii. … but a small influx triggers LTD by activation of
calcium-dependent protein phosphatases
C. LTD in the cerebellum (see Figure 8.17)
1. induction of LTD requires pairing of parallel fiber (cerebellar granule
cell) and climbing fiber activity (climbing fibers provide the ‘learning
signal’; these inputs originate in the inferior olivary nucleus in the
medulla)
2. phenomenon persists for at least many weeks
3. molecular basis of LTD in the cerebellum is different from what occurs in
cerebral cortex
a. induction requires activation of metabotropic glutamate
receptors (rather than NMDA receptors)
b. activation also requires activation of climbing fibers, which
depolarize the membrane, open voltage-gated calcium channels
and ensure a rapid influx of Ca
c. second messenger systems regulated by the metabotropic
glutamate receptors also lead to an increase in intracellular Ca
d. activated PKC (protein kinase C) phosphorylate AMPA receptors
in the cytoplasm, which leads to their internalization from the
postsynaptic membrane
e. thus, in the cerebellum (but not the cerebral cortex!), elevated
intracellular Ca leads to LTD

STUDY QUESTION
Why are NMDA glutamate receptors so important for synaptic plasticity?
A. because the conductance of the channel is voltage-dependent due to the binding of magnesium
to a site on the pore-loop
B. because the channel is permeable to calcium ions
C. because NMDA receptors activate G-proteins on the cytoplasmic surface of the receptor
complex
D. A & B are both especially important
E. A, B & C are all especially important

35
 Overview of Neural Signaling

Medical Neuroscience | Tutorial Notes

Synaptic Plasticity: spike timing-dependent plasticity

MAP TO NEUROSCIENCE CORE CONCEPTS21

NCC2. Neurons communicate using both electrical and chemical signals.
NCC4. Life experiences change the nervous system.
NCC8. Fundamental discoveries promote healthy living and treatment of disease.

LEARNING OBJECTIVES
After study of today’s tutorial, the learner will:
6. Characterize general cellular mechanisms for synaptic change.
7. Discuss the importance of the timing of the postsynaptic response, relative to presynaptic
activity, for synaptic plasticity.

TUTORIAL OUTLINE

V. Introduction
A. plasticity: the capacity of the nervous system to change
C. general cellular mechanisms for synaptic change:
6. neural activity triggers the activation of postsynaptic, second messenger
systems
7. the trigger is usually a specific alteration in the levels of intracellular calcium in
the postsynaptic neuron
8. Ca-dependent second messenger systems alter the activity of protein kinases
(phosphorylate target proteins) and phosphatases (dephosphorylate target
proteins)
9. alterations in protein phosphorylation mediate the early stages of long-term
synaptic plasticity (changes in phosphorylation induce changes in protein
function)
10. the more long-lasting changes in synaptic strength are brought about by
alterations in gene transcription induced by second messenger systems

VI. Spike-timing dependent plasticity (STDP) (see Figure 8.1822)

21
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36
 Overview of Neural Signaling

A. explains how synaptic plasticity can occur in the brain one postsynaptic spike at
a time
- seldom do patterns of neural activity in real brain circuits resemble the
artificial spike trains that were used in the classical studies of the LTP
and LTD
- so, for example, if real synapses seldom (if ever) experience brief trains
of 500 Hz stimulation, how does plasticity (LTP) work?
- STDP provides a framework for understanding how synaptic plasticity
can occur (LTP in this case) without the need for brief, high-frequency
trains of stimulation
B. mechanisms: precision timing matters!
1. synapses strengthen when presynaptic activity precedes postsynaptic
activity by ~20 msec or less
a. this sequence of “pre- before post”, and the short interval
between the two, implicates the presynaptic input in question
as the principal source of depolarization that resulted in the
generation of a postsynaptic action potential
b. this regime is consistent with the Hebbian notion of
“coordination” between pre- and post-synaptic activity (more
on this in next tutorial)
c. for sensory circuits, structured experience with the sensory
environment (e.g., training) may provide one means for
coordinating spatial and temporal patterns of activity
2. synapses weaken when presynaptic activity follows postsynaptic activity
by up to ~40 msec
a. this sequence of “post before pre-” implicates some other
presynaptic input as the principal source of depolarization that
resulted in the generation of a postsynaptic action potential
i. remember that most neurons receives 1000s of
synaptic input
ii. this “post before pre-“ sequence indicates that the
postsynaptic neuron was driven to fire an action
potential by some other input, not the input in question
b. this regime is consistent with the Hebbian notion of
“incoordination” between pre- and post-synaptic activity

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37
 Overview of Neural Signaling

3. note that the interval between pre- and post-synaptic neuron firing that
leads to LTD is roughly twice the interval that leads to LTP
a. this suggests that random firing will tend toward LTD and
the weakening of synaptic connections

b. thus, unstructured activity in sensory circuits would be

expected to favor LTD over LTP

STUDY QUESTION
Which of the following conditions would result in long-term potentiation among connected pre- and
post-synaptic elements?
A. presynaptic spike firing 200 msec before a postsynaptic spike
B. presynaptic spike firing 100 msec before a postsynaptic spike
C. presynaptic spike firing 10 msec before a postsynaptic spike
D. presynaptic spike firing 10 msec after a postsynaptic spike
E. presynaptic spike firing 100 msec after a postsynaptic spike
F. presynaptic spike firing 200 msec after a postsynaptic spike

38
 Overview of Neural Signaling

Medical Neuroscience | Tutorial Notes

Synaptic Plasticity: Hebb’s postulate

MAP TO NEUROSCIENCE CORE CONCEPTS23

NCC2. Neurons communicate using both electrical and chemical signals.
NCC4. Life experiences change the nervous system.
NCC8. Fundamental discoveries promote healthy living and treatment of disease.

LEARNING OBJECTIVES
After study of today’s tutorial, the learner will:
8. Characterize general cellular mechanisms for synaptic change.
9. State Hebb’s postulate and discuss its relevance for neural plasticity.

TUTORIAL OUTLINE

VII. Introduction
A. plasticity: the capacity of the nervous system to change
B. general cellular mechanisms for synaptic change:
11. neural activity triggers the activation of postsynaptic, second messenger
systems
12. the trigger is usually a specific alteration in the levels of intracellular calcium in
the postsynaptic neuron
13. Ca-dependent second messenger systems alter the activity of protein kinases
(phosphorylate target proteins) and phosphatases (dephosphorylate target
proteins)
14. alterations in protein phosphorylation mediate the early stages of long-term
synaptic plasticity (changes in phosphorylation induce changes in protein
function)
15. the more long-lasting changes in synaptic strength are brought about by
alterations in gene transcription induced by second messenger systems

VIII. Hebb’s postulate (see Figure 8.1824)

23
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39
 Overview of Neural Signaling

C. proposed by the Canadian psychologist Donald O. Hebb (1904-1985) in his influential

text, The Organization of Behavior (1949)25
D. the principles of the postulate
- coordinated activity of a presynaptic terminal and a postsynaptic cell would
strengthen the synaptic connection between them
- conversely, uncoordinated activity between synaptic partners would weaken
their synaptic connections
- in short, “neurons that fire together, wire together”
E. changes in synaptic strength (consistent with Hebb’s postulate) are mediated by long-
term potentiation (LTP) and long-term depression (LTD)
F. spike-timing dependent plasticity (STDP) (see Figure 8.18) explains how synaptic change
can occur one spike at a time under physiological conditions in neural networks
1. synapses strengthen when presynaptic activity precedes postsynaptic activity by
~20 msec or less (= coordinated activity)
2. synapses weaken when presynaptic activity follows postsynaptic activity by up
to ~40 msec (= uncoordinated activity)

IX. From synaptic plasticity to circuit plasticity

A. given Hebb’s postulate: “neurons that fire together, wire together”
1. this implies that change at the synaptic level can produces changes in the wiring
patterns of neural circuits
2. synaptic change accumulates (one synapse at a time) throughout a network of
interconnected neurons (recall that a typical cortical pyramidal neuron
maintains about 2,000 synaptic connections with other neurons!)
3. with the strengthening, awakening, and weakening of synaptic connections, and
the addition and deletion of synaptic connections, the net effect of firing or
misfiring together can be wholesale change in the structure and function of
network properties

STUDY QUESTION
Hebb’s postulate is accurately captured by the aphorism coined by my late, great Duke colleague, Larry
Katz, when he proposed: “neurons that fire together, wire together”. This sounds similar to another
aphorism that is often taken as an equally valid restatement of Hebb’s postulate: “use it or lose it”.
Today’s study question is this: is “use it or lose it” an accurate expression that reflects the synaptic
mechanism of neural plasticity?
A. yes
B. no
C. no one knows

25
Read more about D.O. Hebb by clicking here

40
 Overview of the Thalamus

Medical Neuroscience | Tutorial

Overview of the Thalamus

MAP TO NEUROSCIENCE CORE CONCEPTS1

NCC1. The brain is the body's most complex organ.
NCC3. Genetically determined circuits are the foundation of the nervous system.
NCC7. The human brain endows us with a natural curiosity to understand how the world works.

LEARNING OBJECTIVES
After study of today’s learning, the student will:
1. Discuss the embryological origin of the thalamus.
2. Discuss the location of the thalamus in the human brain.
3. Characterize the role of the thalamus in brain function.

TUTORIAL OUTLINE

I. Embryological origin of the thalamus

A. the thalamus is a major part of the diencephalon, which is derived from the prosencephalon
(see Figure 22.3 and A242)
1. the dorsal and posterior part of the diencephalon becomes the thalamus
2. the ventral and anterior part becomes the hypothalamus
3. thus, the thalamus is a component of the forebrain

II. Anatomical localization of the thalamus

A. with respect to the whole brain: the thalamus is near the center of the forebrain (see Figure
A14C; Appendix BoxA (Figure A))
B. relative to the internal capsule: the thalamus is medial to the posterior limb of the internal
capsule (see Figure A14B)
C. relative to the lateral ventricle: the thalamus is the floor of the body of the lateral ventricle
(see Figure A14C)
III. Role of the thalamus in brain function
A. general organization (see Appendix BoxA (Figure A))

1
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1
 Overview of the Thalamus

1. comprised of a large number of distinct nuclei (circumscribed clusters of neurons) that

are bounded by a “Y”-shaped bundle of axons
2. each nucleus sends and receives projections for a different region of the cerebral
cortex:
a. anterior group (in the crook of the “Y”) projects to cingulate gyrus
b. medial group projects to the anterior frontal lobe in front of the motor cortex
(i.e., the prefrontal cortex), the insula and the medial temporal lobe
c. lateral group projects to different regions of the remaining sensory and motor
regions of the cerebral cortex in each lobe
d. additionally, there are smaller nuclei within the fiber bundles that make up the
“Y”; these intralaminar nuclei project diffusely throughout the cerebral cortex
B. principal functions (see Appendix BoxA (Figure B))
1. relay information, in a “feed-forward” fashion, to the cerebral cortex
a. sources of input to specific thalamic relay nuclei
i. for somatic sensation, from the spinal cord and brainstem
ii. for audition and vestibular sensation, from the brainstem
iii. for vision, from the sensory periphery (retina)
iv. for the modulation of movement, from the basal ganglia and the
cerebellum
b. outputs from specific thalamic relay nuclei to the cerebral cortex; these
outputs to the cerebral cortex terminate densely in layer 4 thus defining
unimodal, “primary” cortical areas
i. for somatic sensation, to the postcentral gyrus
ii. for audition, to the superior plane of the temporal gyrus
iii. for vision, to the cortex in the banks of the calcarine sulcus (lingual
and cuneus gyri)
iv. for the modulation of movement, to the motor cortex
2. distributer of higher-order (more processed) signals from one cortical area to another
a. some thalamic nuclei are driven primarily by cortical inputs, rather than
ascending sensory or motor signals
b. these thalamic nuclei, in turn, provide higher-order input that drives activity in
other (non-primary) cortical areas
3. modulators of cortical function
a. the intralaminar and midline thalamic nuclei (sometimes called the “non-
specific thalamic nuclei”) send diffuse projects to the cerebral cortex that
terminate diffusely in upper cortical layers
b. these diffuse projects have modulatory influences over large-scale networks of
cortical neurons that could be important for attention, arousal, mood change,
and transitions in sleep and wakefulness

2
 Overview of the Thalamus

STUDY QUESTION
What are the functions of the thalamus?
A. articulate, compound and communicate
B. relay, distribute, modulate
C. amplify, coordinate and calculate
D. advance, compute and contemplate
E. amplify, compute and communicate

3
 Overview of Cortex and Cortical Circuits

Medical Neuroscience | Tutorial Notes

Overview of Cortex and Cortical Circuits

MAP TO NEUROSCIENCE CORE CONCEPTS1

NCC1. The brain is the body's most complex organ.
NCC3. Genetically determined circuits are the foundation of the nervous system.
NCC7. The human brain endows us with a natural curiosity to understand how the world works.
NCC8. Fundamental discoveries promote healthy living and treatment of disease.

LEARNING OBJECTIVES
After study of today’s learning, the student will:
1. Discuss the embryological origin of the cerebral cortex.
2. Discuss differences in the cytoarchitecture across the cerebral cortex.
3. Discuss the anatomical organization of the cortical microcircuit.
4. Characterize the “ACC” functions of the cortical microcircuit.

TUTORIAL OUTLINE

I. Embryological origin of the cerebral cortex

A. generation and differentiation of neurons and glia

1. nearly all neurons are generated by the middle of the second trimester; thereafter,
only very few neurons are ever generated in the CNS!
2. neuronal and glial genesis occurs in the ventricular zone of the developing forebrain:
the telencephalon, which is derived from the prosencephalon (see Figure 22.32)
a. cell division occurs against the wall of the ventricles where precursor cells
divide and produce other stem cells for many mitotic cycles (see Figure 22.7)
b. some are destined to differentiate into a glial precursors and others into
neuronal precursors, called neuroblasts
3. after many cycles of mitotic activity, some postmitotic neuroblasts migrate away from
the ventricular zone toward the developing cerebral cortex, called the cortical plate
a. many neurons in the CNS are guided to final destinations by glial cells that
span the distance between the ventricular zone and the pia mater

1
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1
 Overview of Cortex and Cortical Circuits

b. for the developing cortical plate, neuroblasts migrate along radial glial cells
(see Figure 22.12)

4. consequently, the cortical plate matures into the cerebral cortex in each hemisphere,
which remains a continuous “sheet” of neural tissue that becomes increasingly folded
into the outer surface of the forebrain

II. Anatomical organization of the cortical microcircuit

A. the continuous “sheet” of neural tissue in each hemisphere is actually multi-layered, with
different layers of neurons and intrinsic connections serving somewhat different purposes
B. the “canonical” cortical microcircuit
1. thalamus projects to (granular) layer 4
a. called “granular” because of the numerous small stellate neurons that are
found in abundance in this layer (see Figure 26.2A)
b. at low magnification, this layer looks like grains of sand (hence the term
“granular”)
2. layer 4 projects to upper (supragranular) layers (2 and 3)
3. upper (supragranular) layers project to lower (infragranular) layers (5 and 6), and to
other cortical areas, including corresponding areas in the opposite hemisphere
4. layer 6 projects up to layer 4, and back down to the thalamus
5. layer 5 projects to the basal ganglia (caudate nucleus and putamen), brainstem and,
for some areas, the spinal cord
C. in addition, there are local connections within each cortical layer
1. each neuron tends to project diffusely to its near neighbors
2. each neuron tends also to project to neurons in surrounding columns that have similar
functional properties (“like connects to like”)

III. The “ACC” of the cortical microcircuit

A. all this circuitry serves to amplify, compute and communicate

1. amplify thalamic input
2. compute additional functional properties that may not be present at antecedent
neural processing centers (e.g., the thalamus)
3. communicate information to other cortical areas and to subcortical centers (e.g.,
thalamus, basal ganglia, brainstem)
B. different divisions (areas) of the cerebral cortex have slight modifications of these basic layers,
which provides for the recognition of anatomical and functional distinctions across the cortex

IV. Cytoarchitecture of the cerebral cortex

A. “cytoarchitecture” refers to the cellular composition of neural tissue

2
 Overview of Cortex and Cortical Circuits

1. recall that neural tissue comprise numerous different types of cells (neurons and glia)
that vary considerably in size and morphology
2. different locations in the cerebral cortex differ in subtle (and sometimes not so subtle)
cytoarchitectonic features
B. around the turn of the 20th century, several important histologists began to stain brain tissue
to reveal the cellular anatomy of neural tissue
1. one important figure in the history of cortical exploration was a German
neuroanatomist, Korbinian Brodmann (1868-1918)3
2. Brodmann studied cortical tissue with a stain that reveals the presence of cell bodies,
called a Nissl4 stain
3. Brodmann famously mapped the cytoarchitecture of the cerebral cortex proposing
some 50 or so divisions based on the cytoarchitecture (e.g., cell density, cell size, layer
thickness, radial organization of cells, etc.) (see Figure 26.2B; Box 26A)
C. differences in the cytoarchitecture of different cortical areas (and differences in the input and
output connections) are the basis for putative differences in the function of cortical areas; a
bold hypothesis proposed by Brodmann and still under investigation for most of the human
cerebral cortex

STUDY QUESTION
The “ACC” of the cerebral cortex is suggested as a useful way of remembering the principal functions of the
cortical microcircuitry. So do you remember? What is the “ACC” of the canonical cortical microcircuit?
A. articulate, compound and communicate
B. amplify, coordinate and calculate
C. advance, compute and contemplate
D. amplify, compute and communicate
E. atlantic coast conference

3
For more on the life and times of Korbinian Brodmann, visit his Wikipedia page by clicking here; and enjoy a unique artistic tribute to
his seminal work at website honoring important European neuroscientists, which you can find here.
4
In neural tissue, Nissl substance is rough endoplasmic reticulum; Nissl substance is found in cell bodies and in the proximal dendrites
of the largest neurons in neural tissue.

3
 General principles of sensory systems

Medical Neuroscience | Tutorial Notes

General principles of sensory systems

MAP TO NEUROSCIENCE CORE CONCEPTS1

NCC1. The brain is the body's most complex organ.
NCC7. The human brain endows us with a natural curiosity to understand how the world works.

LEARNING OBJECTIVES
After study of today’s learning, the student will:
1. Discuss the organization of neuronal pathways in sensory and motor systems.
2. Account for the generation of action potentials in peripheral axons in response to somatic sensory
stimulation.
3. Discuss factors that influence how information is coded in sensory systems.
4. Discuss the concept of the receptive field in sensory processing.

TUTORIAL OUTLINE

I. Overview of sensory and motor systems

A. neuronal pathways
1. series of neurons that transmit information from one location (e.g., sensory surface) to
a distant target (e.g., cerebral cortex)
2. pathways may go in either direction; i.e., ascending from periphery “inwards” (e.g.,
towards cortex; typical of sensory pathways) or descending from cortex “outwards”
(e.g., towards spinal cord; typical of motor pathways)
3. nomenclature for neurons in a pathway
a. first order (primary) neurons
b. second order (secondary) neurons
c. third order (tertiary) neurons
B. all major sensory and motor pathways have midline crossings (= decussations)
1. although the evolutionary perspective on pathway decussations remains opaque, an
important principle of brain function is that each cerebral hemisphere receives sensory
information from the opposite side of the body
2. therefore, each ascending (and descending) pathway must decussate

1
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 General principles of sensory systems

3. but stay tuned … in a forthcoming tutorial, you will learn that cerebellar
representation is ipsilateral!
C. sensory transduction
1. sensory transduction: conversion of the physical (or chemical) energy stimulus into an
electrical signal in a sensory neuron
2. in the somatic sensory system (see Figure 9.22):
A. application of a stimulus deforms the skin and the sensory receptors
embedded within it
B. physical deformation of receptor membranes open ions channels, and sodium
ions (current) flows into receptor ending
C. current depolarizes receptor membrane producing a receptor (or generator)
potential
D. information coding
1. the quality of a stimulus is encoded by the identity of the activated peripheral receptor
(“labeled line” coding scheme)
a. different axonal endings respond to restricted sets of sensory stimuli
i. selectivity is explained by:
- morphological specializations of receptor endings
- properties of the ionotropic channels in receptor membranes
ii. selectivity is conveyed and preserved in parallel pathways in the CNS
2. strength of a stimulus is encoded by:
a. the rate of action potentials in the afferent axons
b. the temporal pattern of action potentials in afferent axons
3. adaptation (see Figure 9.4)
a. all receptors adapt (decrease their firing rate) to the persistent presence of a
stimulus
b. some adapt slowly and display tonic firing patterns as long as a stimulus is
present (more static qualities)
c. others adapt rapidly and display phasic firing patterns (more dynamic
qualities)
4. sensory threshold (see Figure 9.2)
a. all receptors have a sensory threshold for firing action potentials
b. in the somatic sensory system, “threshold” is the strength of mechanical
deformation necessary for producing a generator potential of sufficient
amplitude to elicit an action potential
i. some receptors have a low threshold (e.g., encapsulated endings)
ii. others have a high threshold (e.g., free nerve endings)

2 th
Figure references to Purves et al., Neuroscience, 5 Ed., Sinauer Assoc., Inc., 2012. [click here]

2
 General principles of sensory systems

5. receptive field (see Figure 1.13)

a. region of the body that when stimulated by a mechanical stress elicits a
response in a sensory neuron
i. the center of the receptive field general elicits a robust response
(either a sharp increase or decrease in the firing rate of the neuron)
ii. surrounding the center of the receptive field is a annular region (called
the “surround”) that antagonizes the center zone
b. receptive fields may be defined for any neuron in a sensory pathway
c. for primary neurons, receptive field size is inversely proportional to the
density of their peripheral processes (receptors)
i. thus, large receptive fields are created by large or diffusely distributed
sensory endings
ii. small receptive fields are created by small or spatially restricted
sensory endings
d. for neurons in the cortex, receptive field size is directly proportional to the
degree of convergence in sensory pathways
i. thus, large receptive fields are created by a high degree of
convergence as many inputs from antecedent centers converge on the
dendrites of a single cortical neuron
ii. small receptive fields are associated with minimal convergence of
inputs from antecedent neural centers
e. in mechanosensation, the differential sizes of receptive fields in neurons that
represents different parts of the body accounts, at least in part, for the
differences in two-point discrimination along the body surface (see Figure 9.3)
f. in the cerebral cortex, cognitive factors (e.g., attention, stress) may modify the
size and sensitivity of receptive fields

STUDY QUESTION
What explains regions of high sensory acuity, such as the center of vision or the tips of the fingers?
A. large receptive fields
B. sparsely innervated sensory surfaces
C. densely innervated sensory surfaces
D. small receptive fields
E. both A & B are important for creating high sensory acuity
F. both C & D are important for creating high sensory acuity

3
 Mechanosensation

Medical Neuroscience | Tutorial Notes

Mechanosensation

MAP TO NEUROSCIENCE CORE CONCEPTS1

NCC1. The brain is the body's most complex organ.
NCC3. Genetically determined circuits are the foundation of the nervous system.
NCC7. The human brain endows us with a natural curiosity to understand how the world works.

LEARNING OBJECTIVES
After study of today’s learning, the student will:
1. Identify and characterize the major sensory endings that mediate sensations elicited by touch,
vibration, proprioception, and pain and temperature.
2. Characterize the mapping of the body (somatotopy) in the primary somatic sensory cortex.
3. Discuss the distribution of somatic sensory signals to higher-order processing centers in the parietal
lobe, motor centers, emotional centers and memory centers in the brain.

TUTORIAL OUTLINE

I. Overview of somatic sensory systems2

A. two major, modality-specific subsystems: mechanosensation and pain & temperature
1. a specialized (phylogenetically newer) subsystem for the detection of mechanical
stimuli (e.g., light, discriminative touch, vibration, pressure, movements of muscles
and joints)
2. a more primitive subsystem (phylogenetically older) for the detection of thermal and
potentially harmful (painful or nociceptive) stimuli, and a more crude sense of touch
B. basic functions of somatic sensory systems:
1. identify shape and texture of objects (light touch)
2. detect potentially harmful situations (nociception = “pain perception”)
3. monitor internal and external forces acting on the body
4. contribute to neural representation of self (i.e., proprioception = “self-perception”)
C. basic organization of the somatic sensory systems:

1
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2
For completeness, pain & temperature systems are introduced here, but they will be considered in detail in a separate tutorial.

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 Mechanosensation

1. different types of peripheral receptors mediate the detection of different types

(submodalities) of stimuli in each subsystem
2. two sets of pathways:
a. for the post-cranial body (i.e., below the head and including the posterior
portion of the head)
i. mechanical stimuli: dorsal-column medial lemniscal system
ii. pain and temperature: anterolateral system (and an unusual visceral
pain pathway to be discussed later)
b. for face (and anterior portion of the head)
i. mechanical stimuli: pathway through the principal (chief) sensory
nucleus of the trigeminal complex
ii. pain and temperature: pathway through the spinal nucleus of the
trigeminal complex

II. Mechanosensory processing

A. cutaneous and subcutaneous mechanosensory receptors

1. general organization and function
a. first-order neurons are ganglion neurons (see Figure 9.13)
(i) cell body in dorsal root ganglion or cranial nerve ganglion
(ii) neuronal morphology = “pseudomonopolar”
(iii) diverse endings of peripheral process (axon)
(iv) central process synapses on second-order neurons in CNS
b. functional categories
(i) mechanoreceptors (touch, vibration, pressure)
(ii) nociceptors (pain)
(iii) thermoreceptors (temperature)
c. morphological categories (see Table 9.1)
(i) free nerve endings (pain, temperature)
- supplied by very small diameter, ‘unmyelinated’ C fibers and
lightly myelinated Aδ fibers
(ii) encapsulated endings (touch, vibration, pressure)
- very low threshold for activation
- specializations of large diameter, myelinated fibers
- differ in location in skin, the size of their receptive fields, and
their density in different locations on the body surface
d. mechanism of sensory transduction (see Figure 9.2)

3 th
Figure references to Purves et al., Neuroscience, 5 Ed., Sinauer Assoc., Inc., 2012. [click here]

2
 Mechanosensation

(i) physical deformation of receptor membranes open ion channels, and

current (carried by sodium ions) flows into receptor ending
(ii) current depolarizes receptor membrane producing a receptor (or
generator) potential
e. receptors specialized for tactile discrimination (see Figures 9.5-6 & Table 9.2)
[in Table 9.2 and Figure 9.5, for each of the four afferent systems described, learn the receptive
field size (small vs. large), location, sensory function, effective stimuli, and adaptation rate (slow
vs. rapid)]

a. Meissner’s corpuscles: nerve endings encapsulated by Schwann cell

lamellae
b. Merkel disks: saucer-shaped nerve endings that contact specialized
cells (Merkel cells) between the dermal papillae
c. Pacinian corpuscles: axonal endings encapsulated by a large set of
fluid-filled lamellae (like the layers of an onion)
d. Ruffini corpuscles: nerve endings surrounded by a spindle shaped
capsule
2. receptors specialized for sensing body position (proprioceptors): “self-receptors” that
respond to the mechanical forces arising in the body from the force of gravity and
from active movements
a. muscle spindles (see Figure 9.7A)
(i) small number of intrafusal muscle fibers surrounded by a capsule of
connective tissue in parallel with the extrafusal, striated muscle fibers
(ii) primary sensory endings from group Ia and group II afferent fibers
encircle intrafusal fibers
(iii) both types of afferent fibers are stimulated by stretch applied to the
muscle spindle
b. Golgi tendon organs (see Figure 9.7B)
(i) free nerve endings of group Ib afferent fibers that are woven into the
matrix of collagen fibrils in tendons
(ii) sense the force (tension) generated by muscle contraction
c. joint receptors
(i) mechanosensory afferents distributed around joints
(ii) sense joint motion
B. ascending central pathways for somatic sensation (see accompanying tutorial)

III. Somatic sensory thalamus (see Figure 9.10)

A. the thalamic division that processes mechanosensory signals is the ventral posterior complex
1. receives ascending superficial mechanosensory and deeper proprioceptive information
2. divided into two main nuclei

3
 Mechanosensation

a. ventral posterior lateral nucleus: receives information from the body (below
the head) and posterior head
b. ventral posterior medial nucleus: receives information from the face (and
anterior head)

IV. Somatic sensory cortex (see Figure 9.10)

A. primary somatic sensory cortex: region of the cerebral cortex that first receives the inputs
from the (third-order) neurons in the ventral posterior complex of the thalamus
B. located in posterior bank of central sulcus (postcentral gyrus)
1. includes Brodmann’s Areas 3a, 3b, 1 and 2
2. each subdivision of the primary somatic sensory cortex receives somewhat different
submodalities of mechanosensory input
a. Area 3a: responds primarily to stimulation of “proper” proprioceptors (e.g.,
muscle spindles, joint receptors)
b. Area 3b: responds primarily to simple cutaneous stimuli applied to localized
skin surfaces (e.g., discriminative touch)
c. Area 1: responds to more complex cutaneous stimuli, often involving
stimulation of multiple digits in a certain direction
d. Area 2: responds to both complex tactile and proprioceptive stimuli
3. somatotopy in the primary somatic sensory cortex (see Figure 9.11)
a. each subdivision of the primary somatic sensory cortex contains a complete
“map” of the contralateral sensory surface
b. certain body regions that are especially important for function (hands, face)
are “over-represented”; i.e., receive disproportionate cortical allocation within
the body map (the same is true at subcortical levels)
C. higher-order somatic sensory processing
1. each subdivision of the primary somatic sensory cortex sends axonal projections to the
other subdivisions (see Figure 9.12)
2. these subdivisions, also project to several other important cortical regions:
a. a secondary somatic sensory cortex in the inferior parietal lobe, which itself
contains an entire representation of the body surface
b. the primary motor cortex in the precentral gyrus (and other motor areas in
the frontal lobe), where somatic sensory information is integrated to produce
to appropriate motor behavior
c. regions of the superior parietal lobe where a “schema” of the somatic self is
generated, based on the integration of somatic sensory and visual inputs (and
probably other sensory inputs); this is what is sometimes referred to as the
“body image”
3. higher-order somatic sensory areas project to limbic structures, such as the orbital-
medial prefrontal cortex, the amygdala and the hippocampal formation, where

4
 Mechanosensation

somatic sensory information is integrated with emotional signals (implicit processing)

and memory traces (explicit processing)

STUDY QUESTION
Considering just the consequences for somatic sensation, what do you expect to result from a stroke involving
the right middle cerebral artery?
A. anesthesia over the left side of the body (face, upper extremity, trunk, lower extremity)
B. anesthesia over the right side of the body (face, upper extremity, trunk, lower extremity)
C. anesthesia over the left side of the body below the face
D. anesthesia over the right side of the body below the face
E. anesthesia over the left side of the body below the trunk
F. anesthesia over the right side of the body below the trunk
G. anesthesia over the left side of the face and left arm, but sparing the left leg
H. anesthesia over the right side of the face and right arm, but sparing the right leg

5
 Mechanosensory pathways

Medical Neuroscience | Tutorial Notes

Mechanosensory pathways

MAP TO NEUROSCIENCE CORE CONCEPTS1

NCC1. The brain is the body's most complex organ.
NCC3. Genetically determined circuits are the foundation of the nervous system.

LEARNING OBJECTIVES
After study of today’s learning, the student will:
1. Characterize the organization of the dorsal-column medial lemniscal system from peripheral nerve
ending to cerebral cortex.
2. Recognize components of the dorsal-column medial lemniscal system in the spinal cord,
brainstem, thalamus and cerebral cortex.
3. Characterize the organization of the trigeminal mechanosensory system from peripheral nerve
ending to cerebral cortex.
4. Recognize components of the trigeminal mechanosensory system in the brainstem, thalamus and
cerebral cortex.
5. Characterize the organization of the neural pathways that mediate unconscious proprioception
(“proper proprioception”) from peripheral nerve ending to cerebellum (the spinocerebellar
pathway).
6. Recognize components of the spinocerebellar pathway in the spinal cord and brainstem.

TUTORIAL NARRATIVE

Introduction
There are two major, parallel systems that convey somatic sensory information from the periphery of the post-
cranial body to the cortex, the dorsal column-medial lemniscus system and the anterolateral system. There
are comparable parallel systems carrying information from the face associated with the central projections of
the trigeminal nerve. In addition, there is an important system carrying proprioceptive information from the
muscle spindles to the cerebellum. This tutorial will focus on the pathways taken by the components of the
systems for transmission of neural signals pertaining to the detection and perception of mechanical stimuli. It
is important for your understanding of neurological deficits seen in the clinic to know where these pathways
travel relative to each other and to other structures (including the cranial nerve nuclei) in the brain.

1
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1
 Mechanosensory pathways

Pathways mediating mechanosensation

The pathways that convey information about touch (especially fine, discriminative touch), pressure, and
vibration from the body and face are illustrated in Figures 1 and 2. In the dorsal column-medial lemniscal
system, which carries information from the body, the first order neuron is the dorsal root ganglion cell. The
first-order cells have peripheral processes that are often encapsulated (e.g., Meissner corpuscles, Pacinian
corpuscles) or are associated with specialized receptor cells (e.g., Merkel’s discs). They send central processes
into the spinal cord, where major branches travel in the dorsal columns to the caudal end of the medulla.
There, they synapse on neurons in the dorsal column nuclei, the gracile and cuneate nuclei.
The second-order neurons located in the dorsal column nuclei send their axons across the midline, where they
form a fiber bundle known as the medial lemniscus (hence, the name of this pathway). The axons of the
medial lemniscus run through the rest of the medulla, the pons and the midbrain before ending in the ventral
posterior lateral nucleus (VPL) of the thalamus. Third-order neurons in the VPL send their axons via the
internal capsule to terminate in the somatic sensory cortex, which resides in the postcentral gyrus.
The first-order neurons associated with receptors in the face lie in the trigeminal (Gasserian) ganglion. The
central processes enter the brain via the fifth cranial nerve and terminate in the principal (or chief) sensory
nucleus of the trigeminal complex (or of the fifth nerve). The second-order cells in this nucleus send axons
across the midline to form the dorsal trigeminothalamic tract, also known as the trigeminal lemniscus. These
second-order axons travel to the ventral posterior medial nucleus (VPM) of the thalamus. Third-order neurons
in the VPM send their axons to the postcentral gyrus.

Pathways mediating proprioception

Cutaneous receptors that feed into the dorsal column-medial lemniscal system are one source of information
giving us a sense of body position. A second important source of such information is the pathway leading from
muscle spindles. Two important targets of this information are the postcentral gyrus and the cerebellar cortex,
as illustrated in Figure 3.
The afferent fibers associated with muscle spindles in the legs send their central processes into the spinal cord
where they form synapses in a prominent nucleus in the thoracic and upper lumbar spinal cord, known as the
dorsal nucleus of Clarke. (The axons ascend in the dorsal columns from their point of entry until they reach the
thoracic cord, where they form synapses in this nucleus.) The second-order neurons in Clarke’s nucleus send
very large, heavily myelinated axons into the dorsal-lateral white matter on the same side, where they ascend
as the dorsal spinocerebellar tract. A major target of the spinocerebellar tract, as its name implies, is the
cerebellum. The fibers enter the cerebellum via the inferior cerebellar peduncle. Branches of the
spinocerebellar tract also form synapses on cells in or near the dorsal column nuclei, which appear to then
send axons into the medial lemniscus (joining the pathway already illustrated in Figure 1).
The afferent fibers associated with muscle spindles in the arms send their central processes into a nucleus at
the caudal end of the medulla, known as the external cuneate nucleus (because it lies just lateral to the
cuneate nucleus, already described). The second-order cells send axons into the cerebellum on the same side
via the cuneocerebellar tract, which—like the dorsal spinocerebellar tract—enters the cerebellum via the
inferior cerebellar peduncle.
The functions of these pathways are:
1. to carry information about the length and tension of muscle fibers in the arms and legs to the cerebellum;
2. to provide information to the cerebral cortex that contributes to a sense of position of the limbs and
digits and of the body in space; i.e., a sense of proprioception (“self-awareness”).
The locations of major components of these pathways are indicated in Figure 4.

2
 Mechanosensory pathways

Figure 1. Organization of the central pathways that carry information about discriminative touch, pressure, and
vibration. Information about the body and posterior head is conveyed via the spinal nerves. Information about the
face is conveyed via the fifth cranial nerve. (Illustration by N.B. Cant)

3
 Mechanosensory pathways

Gracile
Cuneate fasciculus
fasciculus

Gracile
Gracile nucleus
Cuneate fasciculus
Cuneate
fasciculus
nucleus

Cervical spinal cord

Internal
arcuate
fibers Caudal medulla

Medial
lemniscus

Middle medulla

Figure 2. Dorsal column-medial lemniscus system, with trigeminal lemniscus, in cross-sections. At the level of the
midbrain, the trigeminal lemniscus joins the medial lemniscus so that all mechanosensory information about the
opposite side of the body (including the head) travels together in topographic order as the tracts approach the
thalamus (stick figure in white lines indicates somatotopic order of tracts; second-order neurons are shown in caudal
medulla section). (Sections from Sylvius4 Online) (Figure continued on next page)

4
 Mechanosensory pathways

Medial
lemniscus

Middle pons

Medial
lemniscus

Midbrain

5
 Mechanosensory pathways

Figure 3. Pathways carrying information from the muscle spindles to the cerebellum and to the cerebral cortex.
(Pathways from the dorsal column nuclei to the thalamus and from there to the cortex are shown in a lighter gray.
This part of the pathway was presented in Figure 1.) (Illustration by N.B. Cant)

6
 Mechanosensory pathways

Dorsal nucleus
of Clarke
Dorsal spinocerebellar Dorsal spinocerebellar
tract tract

Thoracic spinal cord Cervical spinal cord Inferior

cerebellar
Dorsal peduncle
spinocerebellar
tract

Caudal medulla
Middle medulla

Inferior
cerebellar
peduncle

Figure 4. Major components

of the pathways conveying
proprioceptive information to
the cerebellum (second-order
Caudal pons
neuron from Clarke’s nucleus
is illustrated in white).
(Sections from Sylvius4
Online)

7
 Mechanosensory pathways
Pathways for light, discriminative touch, pressure, position sense and vibration.
Pathway Receptors First-order Second-order Third-order neurons Primary cortical area Decussation
neurons neurons pattern
dorsal-column medial  encapsulated endings ipsilateral DRGsi ipsilateral dorsal column contralateral ventral contralateral primary somatic sensory caudal medulla: second-
(Meissner’s & Pacinian nuclei in the dorsal, caudal posterior complex of the cortex (S1) in postcentral gyrus order axons of the
lemniscal system (dorsal root ganglion
corpuscles) neurons) medulla: thalamus: Brodmann’s Areas (BA) 3, 1 & 2 dorsal column nuclei
 specialized receptor  gracile nucleus  ventral posterior lateral cross the midline as the
 lower extremity is represented in the internal arcuate fibers
(for postcranial body, systems (Merkel disks) (VPL) nucleus
(Aβ, Ia & II afferent fibers)  cuneate nucleus paracentral lobule and ascend the
including the posterior
(axons of VPL neurons  upper extremity is represented in the brainstem as the medial
portion of the head)
project to the cerebral Ω-shaped segment of the postcentral lemniscus
cortex via the posterior limb gyrus near the middle of the central
[see Figure 9.8A] of internal capsule) sulcus
 light discriminative touch is first
processed in BA 3b
 deep sensation is first processed in BA
3a

trigeminal (principal)  encapsulated endings ipsilateral “DRGs” ipsilateral principal (chief contralateral ventral contralateral S1 pons: second-order
(Meissner’s & Pacinian  trigeminal ganglion sensory) nucleus of the posterior complex of the axons of the principal
mechano-sensory Brodmann’s Areas 3, 1 & 2
corpuscles) neurons in gasserian trigeminal complex in the thalamus: nucleus cross the
system dorsal-lateral pons  face is represented in the inferior midline and ascend the
 specialized receptor (trigeminal) ganglion  ventral posterior medial segment of the postcentral gyrus
systems (Merkel disks) (VPM) nucleus brainstem as the
(for face—anterior third of  light discriminative touch is first trigeminal lemniscus,
(Aβ, Ia & II afferent (axons of VPM neurons processed in BA 3b which occupies a
head) project to the cerebral
fibers)  deep sensation is first processed in BA position near the dorsal
cortex via the posterior limb and medial edge of the
of internal capsule) 3a
[see Figure 9.8B] medial lemniscus
(supplies a face for
lemniscal homunculus)

spino-cerebellar  muscle spindles ipsilateral DRGs ipsilateral relay nuclei in the Ipsilateral cerebellum None! none through the
 Golgi tendon organs thoracic spinal cord and  cortex  no feedforward processing of sensory circuitry of the
(unconscious) (dorsal root ganglion
neurons) caudal medulla: signals in the cerebral cortex via this cerebellum
proprioception  joint receptors  deep nuclei
 dorsal nucleus of Clarke spinocerebellar pathway; this is why it (remember: there is
(for lower extremity) (via the dorsal is considered “unconscious” ipsilateral
(same neurons that send spinocerebellar and representation in the
(for postcranial body,  external cuneate  however, branches of the
branches to the dorsal cuneocerebellar tracts, cerebellum!)
including the posterior nucleus (for upper spinocerebellar axons synapses on
column-medial lemniscal which form the inferior
portion of the head) extremity) proprioceptive dorsal column neurons
pathway) cerebellar peduncle)
[see Figure 9.9] that do send axons into the medial
lemniscus for “conscious”
proprioception

i
The terms ipsilateral and contralateral will refer to the side of the peripheral or central nervous system relative to the location of the sensory receptors; e.g., cortical representation of the somatic sensory periphery occurs in
the contralateral primary somatic sensory cortex.

8
 Pain Systems

Medical Neuroscience | Tutorial Notes

Pain Systems

MAP TO NEUROSCIENCE CORE CONCEPTS1

NCC1. The brain is the body's most complex organ.
NCC3. Genetically determined circuits are the foundation of the nervous system.
NCC7. The human brain endows us with a natural curiosity to understand how the world works.
NCC8. Fundamental discoveries promote healthy living and treatment of disease.

LEARNING OBJECTIVES
After study of today’s learning, the student will:
1. Discuss the complex phenomenology of pain.
2. Describe two categories of pain sensation (first and second pain) and explain the neural basis of each.
3. Characterize the peripheral and central mechanisms underlying hyperalgesia.
4. Characterize the neural mechanisms for the feedback modulation of nociceptive processing.
5. Characterize the neural mechanisms for the feedforward modulation of nociceptive processing.
6. Discuss the affective dimensions of pain and identify the neural systems that are involved in pain affect
(suffering).

TUTORIAL OUTLINE

I. Introduction: complex phenomenology of pain

A. both sensory (nociception) and affective (emotional unpleasantness) dimensions
B. pain usually engages the emotional systems, both in the short-term and the long-term
C. emotional feelings about the long-term consequences of pain, termed secondary affect,
contribute to the psychosocial aspects of pain management
II. Central processing of pain
A. parallel pathways for nociception
1. first order neurons are ganglion cells (DRGs & V-Gs) with peripheral processes that
terminate as free nerve endings (refer back to Figure 9.52 and Table 9.1)
a. primary axons conduct relatively slowly, with most fibers being small and
many ‘unmyelinated’ or only lightly myelinated

1
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2 th
Figure references to Purves et al., Neuroscience, 5 Ed., Sinauer Assoc., Inc., 2012. [click here]

1
 Pain Systems

b. axons are broadly classified into three groups, which respond to somewhat
different types of painful and/or thermal stimuli
(i) Aδ mechanosensitive nociceptors
- respond to intense or damaging mechanical stimuli
- lightly myelinated; slowly conducting
(ii) Aδ mechanothermal nociceptors
- respond to intense or damaging thermal stimuli
- lightly myelinated; slowly conducting
(iii) C polymodal nociceptors
- respond to thermal, mechanical or chemical stimuli
- unmyelinated; conduct very slowly
c. generally, the receptive fields of nociceptors are relatively large (compared to
innocuous mechanosensory receptors)
d. sensory transduction
i. receptors for nociceptive transduction are members of a large family
of Transient Receptor Potential (TRP) channels
ii. channels are gated by thermal changes, protons (acid), and some
natural compounds (e.g., capsaicin) (see Box 10A)
iii. sensory thresholds can be modified directly and indirectly by
interactions of sensory endings with inflammatory mediators (see
below: peripheral sensitization)
e. central processes of first order neurons enter the dorsal roots and synapse on
local circuit neurons and projection neurons in the superficial dorsal horn
(marginal zone and substantia gelatinosa) and near the base of the dorsal horn
(see Figure 10.3B)
i. as considered below, this local circuitry is important for feedforward
and feedback modulation of nociceptive communication in the CNS
2. there are distinct qualities of pain that are conveyed via parallel central pathways that
originate with these different classes of first order neurons
a. first (sharp) pain
i. early perception of “sharp” pain conveyed by Aδ afferent fibers (see
Figure 10.2)
ii. relayed via the ventral posterior complex of the thalamus to S1, both
of which are somatotopically organized
iii. provides information about acute onset of pain and location of injury
- provides input to segmental spinal reflexes that withdraw limb
from painful stimuli
- provides warning of tissue damage and encourages escape
from source of injury

2
 Pain Systems

b. second pain
i. later, longer-lasting perception of a “dull”, burning type of pain
conveyed by C fibers (see Figure 10.2)
ii. relayed to widespread cortical areas via other thalamic and brainstem
projections, with little somatotopic organization
iii. provides information about ongoing presence of trauma, with little
specification of the location of injured tissues
- may encourage ‘guarding’ or disuse of injured region (e.g.,
promote modified gait to avoid weight-bearing)
- provides input to ‘limbic’ structures in the medial and ventral
forebrain that process the affective dimensions of pain
B. affective dimensions of pain (see Figure 10.5)
1. nociceptive signals reach ‘limbic’ structures in the forebrain, including the anterior
cingulate gyrus, insular cortex, amygdala and orbital-medial prefrontal cortex
a. subcortical inputs arise from brainstem centers and several thalamic nuclei
(outside of the ventral posterior complex)
b. cortico-cortical inputs arise from higher-order somatic sensory areas in the
parietal lobe
2. nociceptive sensations become integrated together with the other somatic and
visceral sensations arising from changes in body state (related to alterations in
autonomic and somatic motor activity) and cognitive processes, all of which gives rise
to the subjective feelings associated with pain
3. ongoing appraisals of these complex somatic and visceral sensations and their long-
term consequences gives rise to secondary affect

III. Visceral Pain

A. visceral pain pathways: conveyed up the neuraxis via a newly discovered pathway in the
dorsal columns of the spinal cord (see Table above)
B. referred pain (see Box 10B)
1. some primary afferents from the viscera synapse on second order neurons in the
dorsal horn that also receive input from more superficial (non-visceral) nociceptors
2. consequently, activation of visceral nociceptors may lead to visceral pain percepts and
percepts associated with peripheral cutaneous fields, a phenomenon known as
“referred pain”
3. convergence may also occur at other gray matter centers along the somatic sensory
pathways (e.g., dorsal column nuclei)

IV. Hyperalgesia (inflammatory pain)

A. enhanced sensitivity to mechanosensory stimulation in a local region surrounding an area of
tissue damage

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 Pain Systems

B. due to peripheral sensitization of nociceptors by paracrine mediators of inflammation (see

Figure 10.7)
1. mediate immune response to injury and increase in local perfusion of damaged tissues
2. increase the sensitivity of nearby nociceptors by directly altering sensory transduction
at the TRP receptors
3. activate second messenger systems within the terminal endings of the nociceptors
4. release of neuropeptides by the nociceptor ending itself, which in turn, facilitate the
local inflammatory response
5. these diverse mechanisms are potential targets for pharmaceutical intervention (e.g.,
aspirin inhibits synthesis of prostaglandins)
C. central sensitization may also contribute to hyperalgesia
1. activity-dependent increase in the excitability of second-order neurons (dorsal horn)
following high levels of nociceptor activity
2. may generalize to other sources of input to second-order neurons
a. some primary nociceptive afferents synapse on second order neurons in the
dorsal horn that also receive input from mechanosensory afferents
b. should such second-order neurons become sensitized, an innocuous input may
become painful (= allodynia)
3. two mechanisms of central sensitization (a form of LTP):
a. transcription independent (“wind-up”)
i. repeated activation of nociceptors leads to a sustained depolarization
of the second–order neuron
ii. postsynaptic conductances gated by glutamate become more effective
in depolarizing neurons
b. transcription dependent
i. activation of second messenger systems may lead to changes in gene
transcription that increase the excitability of the second-order neuron
V. Central Regulation of Nociception and Pain
A. analgesia: the absence of pain in the presence of a nociceptive stimulus
B. the perception of pain is subject to a broad range of modulatory influences
1. contextual influences
a. emotional context of trauma (e.g., stress) can heighten or diminish sensations
of pain
b. cognitive understanding (“expectation”) can similarly shape the experience of
pain (e.g., the placebo effect, exercise)
c. cultural differences in a person’s response to painful stimuli
d. at least some of these influences may be explained by “descending” neural
pathways that modulate the central transmission of nociceptive information
2. feedback (descending) modulation of nociception

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 Pain Systems

a. higher centers, including the somatic sensory cortex, the limbic forebrain and
hypothalamus, project to groups of neurons in the brainstem that modulate
that primary transmission of nociceptive signals (see Figure 10.8A)
i. descending projections from the telencephalon target (among many
sites) the periaqueductal gray of the midbrain
ii. these midbrain structures in turn project to serotonergic neurons in
the pontine Raphe nuclei, noradrenergic neurons in the locus
coeruleus (pons), and portions of the reticular formation in the
ventral lateral medulla
iii. neurons in these brainstem regions project to the dorsal horn of the
spinal cord and the spinal trigeminal nucleus
iv. some of these neurons release a wide variety of excitatory and
inhibitory neurotransmitters, including biogenic amines (serotonin,
norepinephrine), that can activate local circuit neurons in the dorsal
horn that release opioids (endorphins, enkephalins, dynorphins)
v. the analgesic effects of opioids in the dorsal horn are due to the
interruption of nociception at the first synapse in the pathway
vi. opioids also have more widespread analgesic actions by modulating
descending systems, as well as cortical neurons that generate painful
perceptions (opioid receptors are widespread in the CNS)
vii. perhaps the placebo effect (an other related phenomena that
manipulate “expectation”) is mediated by endogenous opioids acting
upon this descending modulatory system
3. feedforward modulation of nociception: “gate theory” of pain
a. central idea: pain results from the balance of activity in nociceptive and non-
nociceptive afferents
b. activation of non-nociceptive inputs inhibits firing of second-order neurons by
activating an inhibitory interneuron (see Figure 10.8B)
c. non-nociceptive inputs ‘close’ the gate and prevent pain transmission

VI. Chronic Pain

1. nociceptive chronic pain
a. results from ongoing stimulation of nociceptors
b. involves both first and second pain
2. chronic pain syndromes
a. typically, chronic pain with no known nociceptive etiology
b. common examples: chronic lower back pain, fibromyalgia
c. etiology remains poorly defined
d. recent proposals include dysregulation of descending modulatory systems
(e.g., diminished input to periaqueductal gray)

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 Pain Systems

VII. Neuropathic Pain

A. results from abnormal patterns of activity in nociceptive pathway unrelated to the
presence of a noxious stimulus in the periphery
B. peripheral causes (e.g., nerve compression, inflammation)
C. accompanied by abnormal somatic sensations
D. may involve abnormal activity in sympathetic nervous system
E. may have central nervous system causes
1. sustained sensitization of neurons in the nociceptive pathway
2. plasticity at higher levels of somatic sensory and motor representation (e.g.,
phantom limb pain; see Box 10D)

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 Pain  Pathways  •  Spring  2013  

Medical  Neuroscience  |  Tutorial  

Pain  Pathways  

MAP  TO  NEUROSCIENCE  CORE  CONCEPTS1  

NCC1.   The  brain  is  the  body's  most  complex  organ.  
NCC3.   Genetically  determined  circuits  are  the  foundation  of  the  nervous  system.  
NCC7.   The  human  brain  endows  us  with  a  natural  curiosity  to  understand  how  the  world  works.  
NCC8.   Fundamental  discoveries  promote  healthy  living  and  treatment  of  disease.  

LEARNING  OBJECTIVES  
After  study  of  today’s  learning,  the  student  will:  
1. Characterize  the  organization  of  the  anterolateral  system  from  peripheral  nerve  ending  to  cerebral  
cortex.  
2. Recognize  components  of  the  anterolateral  system  in  the  spinal  cord,  brainstem,  thalamus  and  
cerebral  cortex.2  
3. Characterize  the  organization  of  the  trigeminal  pain  &  temperature  (spinal  trigeminal)  system  from  
peripheral  nerve  ending  to  cerebral  cortex.  
4. Recognize  components  of  the  trigeminal  pain  &  temperature  (spinal  trigeminal)  system  in  the  
brainstem,  thalamus  and  cerebral  cortex.1  

TUTORIAL  NARRATIVE  

Introduction  
There  are  two  major,  parallel  systems  that  convey  somatic  sensory  information  from  the  periphery  of  the  post-­‐
cranial  body  to  the  cortex,  the  dorsal  column-­‐medial  lemniscus  system  and  the  anterolateral  system.  There  
are  comparable  parallel  systems  carrying  information  from  the  face  associated  with  the  central  projections  of  
the  trigeminal  nerve.  In  addition,  there  is  an  important  system  carrying  proprioceptive  information  from  the  
muscle   spindles   to   the   cerebellum.   This   tutorial   will   focus   on   the   pathways   taken   by   the   components   of   the  
systems   for   transmission   of   neural   signals   pertaining   to   pain   and   temperature   sensation.   It   is   important   for  
your  understanding  of  neurological  deficits  seen  in  the  clinic  to  know  where  these  pathways  travel  relative  to  
each  other  and  to  other  structures  (including  the  cranial  nerve  nuclei)  in  the  brain.  
 

   

1
  Visit  BrainFacts.org  for  Neuroscience  Core  Concepts  (©2012  Society  for  Neuroscience  )  that  offer  fundamental  principles  about  the  
brain  and  nervous  system,  the  most  complex  living  structure  known  in  the  universe.  
2
  As  you  study  somatic  sensory  pathways,  you  should  begin  referring  to  cross  sections  through  the  nervous  system  (e.g.,  in  Sylvius4)  so  
that  you  can  recognize  where  relevant  nuclei  and  axonal  tracts  are  located  within  the  brain  and  spinal  cord.  

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 Pain  Pathways  •  Spring  2013  

Pathways  mediating  pain  and  temperature  sensation.  

The  anterolateral  system  is  responsible  for  conveying  information  about  pain,  temperature  and  crude  touch  
(i.e.,   touch   lacking   the   spatial   resolution   of   the   dorsal   column   system)   from   the   post-­‐cranial   body.   Comparable  
information   about   the   face   is   processed   in   trigeminal   pathways.   These   pathways   are   illustrated   in   Figures   1  
and  2.  Most  peripheral  processes  associated  with  the  dorsal  root  ganglion  cells  that  contribute  to  this  system  
are  “free.”  That  is,  they  are  not  associated  with  encapsulated  endings  like  those  in  the  dorsal  column-­‐medial  
lemniscal   system.   In   addition,   the   first-­‐order   fibers   associated   with   the   anterolateral   system   are   generally  
much   smaller   in   diameter   than   those   associated   with   the   dorsal   column   system.   (So   what   does   this   tell   you  
about  the  relative  conduction  velocities  of  these  two  important  somatic  sensory  pathways?)  
The  first-­‐order  neurons  in  the  anterolateral  system,  like  those  in  the  dorsal  column-­‐medial  lemniscal  system,  
have  their  cell  bodies  in  the  dorsal  root  ganglia.  The  central  processes  of  these  neurons   terminate  on  second-­‐
order  neurons  in  the  dorsal  horn  of  the  spinal  cord.  Pain  and  temperature  information  from  receptors  in  the  
face   is   carried   into   the   brain   on   the   fifth   nerve.   The   cell   bodies   of   the   first   order   neurons   are   in   the  trigeminal  
ganglion   and   the   central   processes   of   the   cells   make   synapses   in   a   nucleus   in   the   medulla   known   as   the  spinal  
trigeminal   nucleus  (of  the   fifth   nerve).   This   nucleus   is   actually   continuous   with   the   dorsal   horn   of   the   spinal  
cord.  
The  second-­‐order  neurons  in  the  dorsal  horn  of  the  spinal  cord  send  their  axons  across  the  midline,  where  they  
accumulate  in  the  anterolateral  (ventrolateral)  part  of  the  white  matter.  They  ascend  in  this  location  through  
the   length   of   the   cord.   Many   of   these   fibers   continue   through   the   medulla,   the   pons   and   the   midbrain   to  
contact   third-­‐order   neurons   in   the   ventral   posterior   lateral   (VPL)   nucleus   of   the   thalamus   (as   well   as   other  
thalamic   nuclei).   This   direct   pathway   from   the   spinal   cord   to   the   thalamus   is   often   called   the   spinothalamic  
tract.  Actually,  the  thalamus  is  only  one  of  the  targets  of  the  second-­‐order  neurons  in  the  anterolateral  system.  
These   neurons   also   project   to   central   parts   of   the   medulla,   pons   and   midbrain   known   collectively   as   the  
reticular  formation  (this  component  of  the  anterolateral  system  is  known  as  the  “spinoreticular  tract”)  and  to  
the   periaqueductal   gray   matter   and   the   superior   colliculus   (this   component   is   known   as   the  
“spinomesencephalic  tract”).  Second-­‐order  neurons  located  in  the  spinal  trigeminal  nucleus  send  their  axons  
across  the  midline  to  form  the  ventral  trigeminothalamic  tract,  which  travels  to  the  ventral  posterior  medial  
(VPM)  nucleus  of  the  thalamus.  
Third-­‐order  neurons  in  the  ventral  posterior  nucleus  and  in  other  thalamic  nuclei  then  project  to  the  cortex  via  
the   internal   capsule.   The   postcentral   gyrus   appears   to   be   important   for   the   ability   to   discriminate   the   exact  
location  of  painful  stimuli,  but  many  other,  less  well-­‐understood  cortical  areas  (including  areas  in  the  anterior  
part  of  the  cingulate  gyrus)  appear  to  be  important  in  the  complete  sensation  of  pain,  including  the  complex  
affective  dimensions  of  pain.  
Figure   3   presents   a   diagram   of   the   major   parallel   pathways   carrying   somatic   sensory   information   to   the  
cerebral  cortex  (see  tutorial  notes  on  “Mechanosensory  Pathways”).  The  pathways  for  mechanoreception  
and  the  pathways  for  pain  and  temperature  sensation  shown  in  Figure  A1  are  shown  together  bilaterally.  
 
   

2
 Pain  Pathways  •  Spring  2013  

 
 

 
Figure  1.  Organization  of  the  central  pathways  for  pain  and  temperature  sensation.  These  pathways  also  carry  crude  
information  about  touch.  (As  discussed  an  earlier  tutorial,  there  is  a  small  input  into  the  trigeminal  nuclei  from  the  
seventh,  ninth  and  tenth  nerves,  but  this  input  is  of  little  significance  clinically.)  (Illustration  by  N.B.  Cant)  
   

3
 Pain  Pathways  •  Spring  2013  

 
 
 
Spinal   Spinal  
  Dorsal   trigeminal   trigeminal  
horn   tract   nucleus  
 
 
 
 
 
Anterolateral  
  Cervical  spinal  cord   system   Anterolateral  
  system  

  Caudal  medulla  

 
 
 
 
Spinal  
Region  of  ventral   Spinal  
  trigeminal  
trigeminothalamic   trigeminal  
tract  
  tract   nucleus  

 
 
 
 
Anterolateral  
  system
 
 
 
  Middle  medulla  
 
 
Figure   2.   Location   of   the   anterolateral   system   in   the   cervical   cord   and   brainstem,   with   the   ventral  
trigeminothalamic  tract,  as  seen  in  cross-­‐sections.  Note  that  at  all  levels,  the  fibers  of  both  tracts  are  located  in  
the  anterolateral  part  of  the  brainstem  tegmentum  (second-­‐order  neurons  are  illustrated  in  white).  (Sections  
from  Sylvius4)  (Figure  continued  on  next  page)  
   

4
 Pain  Pathways  •  Spring  2013  

 
 
Spinal  trigeminal  
nucleus  &  tract  
Region  of  ventral  
trigeminothalamic  tract  

Anterolateral  
system  

Caudal  pons  
 
 
 
 
Region  of  ventral  
  trigeminothalamic  tract  

Midbrain   Anterolateral  
system  

 
 
   

5
 Pain  Pathways  •  Spring  2013  

 
 
Figure  3.  A  diagram  of  the  major  parallel  pathways  carrying  somatic  sensory  information  to  the  cerebral  cortex.  
The  pathways  for  mechanoreception  and  the  pathways  for  pain  and  temperature  sensation  are  shown  together  
bilaterally  in  this  figure.  See  related  figures  labels  of  nuclei  and  tracts.  (Illustration  by  N.B.  Cant)  
 

6
 The Eye

Medical Neuroscience | Tutorial Notes

Visual System: The Eye

MAP TO NEUROSCIENCE CORE CONCEPTS1

NCC1. The brain is the body's most complex organ.
NCC3. Genetically determined circuits are the foundation of the nervous system.
NCC7. The human brain endows us with a natural curiosity to understand how the world works.

LEARNING OBJECTIVES
After study of the assigned learning materials, the student will:
1. Describe the factors and neural mechanisms that account for the focusing of an image on the
retina.
2. Identify the five neuronal cell types of the retina and state the roles of each in retinal
processing.
3. Characterize the molecular processes that underlie phototransduction.
4. Discuss the responses of retinal ganglion cells to the onset and offset of light and the relevance
their receptive fields for the detection of light and shadow.

TUTORIAL OUTLINE

I. Review the gross anatomy of the human eye (see Figure 11.12)

II. Formation of optical images

A. refraction: “bending” of light that occurs at the interface of different optical media
1. most (~80%) of refraction occurs as light passes through the cornea
2. sharp focusing of images at variable distances from the eye requires an
adjustable lens, by a process called accommodation
B. accommodation
1. dynamic changes in the refractive power of the lens
a. when the lens is flat … least refractive power (far vision)
b. when lens is rounded … most refractive power (near vision)
2. control of lens shape (see Figure 11.2)

1
Visit BrainFacts.org for Neuroscience Core Concepts (©2012 Society for Neuroscience ) that offer fundamental principles
about the brain and nervous system, the most complex living structure known in the universe.
2 th
Figure references to Purves et al., Neuroscience, 5 Ed., Sinauer Assoc., Inc., 2012. [click here]

1
 The Eye

a. lens is an elastic structure that tends to round up

b. the lens is attached to the circular ciliary muscle by an array of zonule
fibers; the resting tension exerted by the zonule fibers is sufficient to
pull the lens into a flattened position
c. to focus on a near object, the lens must become more rounded, which is
accomplished by the contraction of the ciliary muscle
(i) contraction of the circular ciliary muscle brings the attachment
points of the zonule fibers closer to the lens
(ii) this relieves tension on the lens and the lens’s intrinsic elasticity
allows it to round up
3. adjustments of pupil size also contribute to focusing of images on the retina
a. because optical aberrations are greatest as light passes through the
edges of the lens, the pupil minimizes these errors by restricting the
passage of light to the center of the lens
b. a very small pupil severely limits the amount of light entering the eye,
which may be detrimental under conditions of dim illumination
c. the neural control over pupil size (see Figure 12.2) provides for a
optimization of these two competing considerations under varying
conditions of illumination

III. Inner layer of the eye

A. comprises two tissues derived from the developing diencephalon (see Figure 11.4)
1. neural retina (see below)
2. pigment epithelium (see Figure 11.6)
a. tissue containing the pigment, melanin (albino individuals lack this
pigment and are highly “light sensitive”)
b. reduces the back scattering of light
c. absorbs photoreceptor disk membrane and recycles photopigment
d. photoreceptors become dysfunctional and eventually nonfunctional if
separated from the pigmented epithelium (e.g., retinal detachment)
B. basic wiring diagram of the retina (see Figure Figure 11.5)
1. five neuronal cell types stacked into five histological layers of alternating cell
bodies and neuropil (cellular processes and synapses)
a. direct flow of information mediated by a three-neuron chain:
(i) photoreceptors: main sensory transducers in retina; two basic
types: rods and cones (generate graded potentials)
(ii) bipolar cells: interneurons between photoreceptor and
ganglion cells (generate graded potentials)

2
 The Eye

(iii) ganglion cells: integrates electrical activity from bipolar (and

amacrine) cells and gives rise to axons that form the optic
nerve; only cell class in retina that fires action potentials
b. lateral interactions mediated by two cell types:
(i) horizontal cells: mediate lateral interactions between
photoreceptors and bipolar cells
(ii) amacrine cells: mediate lateral interactions between bipolar
cells, other amacrine cells and ganglion cells
2. in addition, there is specialized type of glial cell (called the Müller cell) that helps
to maintain the ionic environment across the retina
3. light path: through the retinal layers!

IV. Phototransduction
A. in the dark, photoreceptors are depolarized (to about -40 mV) and are continuously
releasing their neurotransmitter, which is glutamate
1. cation-selective ion channels in the outer segments of the photoreceptors are
gated by cytoplasmic cGMP (see Figure 11.8)
2. in the dark, cGMP levels are high and cations flow into the outer segments
(called the “dark current”), keeping the cell in a depolarized state
B. effects of light
1. photopigments
a. in the membranous disks of the outer segments there are a variety of
photopigment molecules that consist of two subunits:
(i) a light-absorbing component, 11-cis retinal
(ii) any one of a number of opsin proteins that fine-tune the
molecular absorption of 11-cis retinal
b. the best known photopigment is rhodopsin, the pigment of rods
c. cones have one of three photopigments that are sensitive to short,
medium or long wavelengths of light (see Figure 11.14)
2. when light strikes the outer segments, photoreceptors hyperpolarize (to about -
65 mV) and release much less glutamate (see Figure 11.8-11.10)
a. absorption of a photon of light by rhodopsin leads to a conformation
change and the activation of a G-protein, called transducin
b. transducin activates a phosphodiesterase that hydrolyzes cGMP
c. cGMP concentrations in the outer segment fall and the cation-selective
channels close, which leads to hyperpolarization
3. amplification: this complex second messenger cascade allows for great
amplification of the initial event

3
 The Eye

V. Rods and Cones (see Figure 11.11-11.13)

A. rods: very low spatial resolution, but extremely sensitive to light
1. large outer segments in a rod-like shape maximizes the amount of
photopigment that can be contained and made available for transduction
2. greater molecular amplification in transduction cascade; sensitive to 1 photon
(cones typically require about 100 photons to become activated)
3. predominant type of photoreceptor across the retina, except for the fovea
4. convergence pattern: the ratio of rods to ganglion cells is relatively high (signals
derived from many rods converge onto the same ganglion cell)
B. cones: very high spatial resolution, but relatively insensitive to light
1. different cones with different absorption spectra make color vision possible
2. convergence pattern: the ratio of cones to ganglion cells is very low,
approaching 1 to 1 in the fovea (= “pit”), a specialized part of the retina where
cones are very dense and visual acuity is greatest
C. rods and cones make different contributions to visual activity
1. scotopic vision: very low levels of illumination when only rods are activated
2. mesopic vision: low levels of illumination (e.g., under moonlight) when both
rods and cones are activated
3. photopic vision: moderate and high levels of illumination when rods are
saturated and only cones are activated
VI. Ganglion cell receptive fields
A. receptive field (in the visual system): region of visual space (or region of the retina) that
when illuminated or darkened elicits a response in a visual sensory neuron
B. center-surround structure of ganglion cell receptive fields (see Figure 11.17)
1. center: small circular region
a. ON center: ganglion cell increases its firing rate when light falls on the
center of the its receptive field
b. OFF center: ganglion cell decreases its firing rate when light falls on the
center of its receptive field
2. surround: larger annulus surrounding the receptive field center
a. surround antagonizes the center
(i) ON center cells have OFF surrounds
(ii) OFF center cells have ON surrounds
c. OFF surround: firing rate decreases when light falls on the surround
d. ON surround: firing rate increases when light falls on the surround
3. center/surround design allows for increased sensitivity to luminance contrast,
such as the edge of shadow (see Figure 11.19)

4
 The Eye

C. retinal circuitry underlying ganglion cell receptive fields

1. receptive field structure is generated in the outer plexiform layer, by the
interactions of photoreceptors, bipolar cells and horizontal cells
2. two physiological classes of bipolar cells define the center response type of
ganglion cells (see Figure 11.18)
a. ON center bipolar cells hyperpolarize in response to the glutamate
released by photoreceptors, due to the activation of metabotropic
receptors and their related second-messenger systems
b. OFF center bipolar cells depolarize in response to glutamate released by
photoreceptors, due to activation of AMPA receptors
c. bipolar cells respond with graded potentials, not action potentials
(i) they release more neurotransmitter when depolarized
(ii) they release less neurotransmitter when hyperpolarized
So now consider what happens when light strikes the center of a ganglion cell’s receptive
field center. Be prepared to explain why ON-center ganglion cells increase their activity and
OFF-center ganglion cells decrease their activity in terms of the neurophysiology of bipolar
cells in the middle of the retina.

3. lateral interactions mediated by horizontal cells account for center-surround

antagonism

LEARNING OBJECTIVES
Q1. In order to properly fixate nearby, stationary visual targets and focus their images on the retina,
each of the following actions listed below usually occurs, EXCEPT for one. Identify the action
that IS NOT part of the normal response to visual fixation.
A. the shape of the lens in each eye is altered
B. vergence eye movements (convergence or divergence)
C. the firing rate of brainstem neurons that govern iris constrictor muscles is altered
D. the shape of the cornea in each eye is altered
E. the diameter of the pupils is altered

Q2. Which of the following natural stimulus configurations provides the BEST stimulus for an OFF-
center ganglion cell?
A. uniform illumination across the entire receptive field
B. the edge of a shadow that falls across the border between the center and surround of
the receptive field, with the center region in shadow
C. a small spot of light that falls within the surround region
D. the edge of a shadow that falls across the border between the center and surround of
the receptive field, with the center region illuminated
E. uniform shadow across the entire receptive field

5
 Central Visual Processing

Medical Neuroscience | Tutorial Notes

Visual System: Central Visual Processing

MAP TO NEUROSCIENCE CORE CONCEPTS1

NCC1. The brain is the body's most complex organ.
NCC3. Genetically determined circuits are the foundation of the nervous system.
NCC7. The human brain endows us with a natural curiosity to understand how the world works.

LEARNING OBJECTIVES
After study of the assigned learning materials, the student will:
1. Describe the distribution of the axons of retinal ganglion cells to major processing centers in the
forebrain and brainstem.
2. Discuss the major receptive field properties of V1 neurons.
3. Discuss the functions of parietal and temporal “extrastriate” visual pathways.

TUTORIAL OUTLINE

I. Functional organization of V1
A. the primary visual cortex (V1) is also known as the “striate cortex”
1. “striate” because of a prominent band of white matter (stria of Genari) that
runs through the middle of cortical layer 4, giving this region of the cortex a
distinctive appearance
2. Brodmann recognized this cortical region as Area 17
B. neurons in V1 show response properties that are not elaborated at previous stages of
neural processing (some of the best examples of “computational” functions of the
cerebral cortex are known from neurophysiology studies of V1)
C. receptive field properties of cortical neurons in V1
1. V1 neurons respond best to moving edges of light and shadow
a. small spots of light that evoke vigorous discharges in retinal ganglion
cells and LGN neurons are not very effective in driving V1 neurons
b. V1 neurons respond best to a moving edge that is within a narrow range
of orientations in space (e.g., horizontal, vertical, oblique); this property
is known as orientation selectivity (see Figures 12.8, 12.10 & 12.122)

1
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 Central Visual Processing

c. many V1 neurons respond best when a particular orientation moves in

only one direction (e.g., a vertical edge moving from right to left); this
property is known as direction selectivity
2. ocularity
a. the retinal inputs to the LGN terminate in separate layers, so that
individual neurons in the LGN are monocular
b. the projections of these monocular LGN neurons to layer 4 of V1 remain
segregated within layer 4 (see Figure 12.13)
(i) LGN afferents terminate in alternating bands or columns in layer
4, called ocular dominance columns
(ii) monocular neurons in the ocular dominance columns of layer 4
converge onto neurons in layers 2 and 3, where binocularity is
first established in the visual pathway
3. stereopsis
a. because neurons in V1 (after layer 4) are binocular, neural signals are
generated that take advantage of the fact that, for near objects, the
lines of sight of the two eyes are slightly different (see Figure 12.14)
b. for all objects near or far from the plane of fixation, images of the
objects fall on “non-corresponding” locations in the two retinas
c. many cells in V1 (and in other visual cortical areas) are sensitive to such
retinal disparities
d. these neural signals are the basis of stereopsis, which provides one
important cue about the location of objects in depth (this
computational property in V1 is necessary for the 3D effect in visual
media!)
e. other cues about depth include motion parallax and size constancy
D. parallel pathways
1. there are distinct anatomical and physiological classes of retinal ganglion cells,
each of which is organized into ON and OFF center-surround subtypes
2. three important classes are the M, P and K ganglion cells (see Figure 12.15)
a. M ganglion cells have larger cell bodies, dendritic arbors and axons
compared to P cells; thus, M cells have larger receptive fields and their
axons conduct faster than P cells
b. M cells respond transiently (phasically) to visual stimuli, while P cells
show a more sustained (tonic) response
c. P cells are sensitive to color, while M cells are “color-blind”
(i) receptive field centers and surrounds of P cells are driven by
different types of cones (e.g., red and green)

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 Central Visual Processing

(ii) P cells respond best to differences in color striking their centers

and surrounds (e.g., red center and green surround)
(iii) the centers and surrounds of M cells are both driven by
different types of cones
3. M and P ganglion cells terminate in different sets of layers in the LGN, the
magnocellular (“large cell”) layers (layers 1 and 2) and parvocellular (“small
cell”) layers (layers 3-6), respectively
4. In V1, the inputs from magnocellular and parvocellular LGN neurons are partially
segregated into functional “streams” of processing, a magnocellular stream for
detecting quickly moving stimuli and a parvocellular stream for detailed
examination of form (acuity) and color (see below)
5. there are also K ganglion cells that project to small clusters of “konio” cells that
reside between the major laminae of the LGN; this so-called koniocellular
pathway is conveyed to V1 in projections that terminate in patches in layer 2/3
(an exception to the thalamus-to-layer 4 rule)
VIII. Extrastriate Visual Cortex
A. beyond V1 (= “striate cortex”), there are multiple areas in the occipital, parietal and
temporal lobes that process visual information (see Figure 12.16-12.18)
B. these areas are arranged into two broad functional pathways that feed visual
information from V1 into associational cortical areas in the parietal and temporal lobes
(see Figure 12.18):
1. dorsal or lateral parietal pathway: responsible for spatial aspects of vision, such
as the relationships between objects and ourselves and the movements of
objects (including ourselves) through the environment (i.e., “where?”)
2. ventral or inferior temporal pathway: responsible for high-resolution form
vision, color processing and object recognition (i.e., “what?”)
C. although both pathways receive input from both parvocellular and magnocellular
streams in V1, there tends to be more ‘magnocellular’ influence on the parietal pathway
and more ‘parvocellular’ influence on the temporal pathway
D. damage to cortical areas in the parietal and temporal pathways produce different visual
deficits, such as the selective loss of color vision or an inability to recognize a familiar
face (ventral temporal pathway), or the loss of motion perception (parietal pathway,
involving lesions in visual areas MT/MST in particular)

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 Central Visual Processing

STUDY QUESTION
The primary visual cortex (V1) performs a number of important functions in visual encoding and visual
perception. However, which of the following functions is best attributable to higher-order visual cortical
areas beyond V1?
A. the recognition and identification of complex visual stimuli, such as human faces
B. provision of neural input to the parietal and temporal visual processing streams
C. binocular vision; i.e., bringing together in a binocular pathway the neural signals derived
from the two eyes
D. stereopsis; i.e., computations about depth based on slight differences in the views of
the two eyes
E. the analysis of simple elements of visual stimuli, such as the orientation of contours,
their direction of motion, and their location in visual space

4
 Central Visual Pathways

Medical Neuroscience | Tutorial Notes

Visual System: Central Visual Pathways

MAP TO NEUROSCIENCE CORE CONCEPTS1

NCC1. The brain is the body's most complex organ.
NCC3. Genetically determined circuits are the foundation of the nervous system.

LEARNING OBJECTIVES
After study of the assigned learning materials, the student will:
1. Describe the distribution of the axons of retinal ganglion cells to major processing centers in the
forebrain and brainstem.
2. Discuss the topographic representation of visual space in the primary visual cortex (V1) and its
anatomical basis in the organization of visual projections.
3. Discuss the distribution and functions of parietal and temporal “extrastriate” visual pathways.

TUTORIAL OUTLINE

I. Overview of Central Visual Pathways

A. central projections of the retina arise from retinal ganglion cells
B. projections terminate on a variety of structures in the diencephalon and midbrain (see
Figure 12.12 for gross overview)
1. diencephalic targets
a. dorsal lateral geniculate nucleus (LGN)
(i) principal target of retinal ganglion cells
(ii) relays visual signals to the primary visual cortex (V1)
(iii) this pathway, is responsible for most aspects of what we know
as visual perception
b. suprachiasmatic nucleus of the hypothalamus
(i) responsible for entraining endogenous circadian (daily) rhythms
to natural day-night cycle

1
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 Central Visual Pathways

(ii) the light-sensing elements in this visual projection are a special

class of photosensitive ganglion cells that contain another
photopigment, melanopsin
2. midbrain targets
a. superior colliculus
(i) involved in coordinating orienting movements of the head and
eyes to a visual stimulus (and other sensory stimuli)
b. pretectum
(i) involved in pupillary light reflex (see Figure 12.2)
See tutorial on “Visual System – Pupillary Light Reflex”.
Be sure that you know the neuroanatomical basis of the pupillary light
reflex and what can be learned about the integrity of the nervous system
as you consider the possible outcomes of this test (e.g., constriction of the
left eye, but not the right eye, when light is presented to the right eye,
vice versa, etc.)

(ii) pretectum is also involved in coordinating the activities of the

preganglionic neurons that innervate the ciliary muscles and
allow for accommodation
C. parallel processing in visual pathways begins with distinct anatomical and physiological
classes of retinal ganglion cells and continues into the array of cortical areas that
process different aspects of visual information

II. The pathway from the retina to V1 in more detail

A. from retina to brain (see Figure 12.1)
1. ganglion cell axons leave the retina at the optic disk and project centrally in the
optic nerve (“CN” II—not really a nerve, but an extension of the brain)
2. about 55% of the optic nerve axons cross the midline (i.e., decussate) in the
optic chiasm and project to the contralateral hemisphere; the other 45% remain
ipsilateral (see below for consideration of retinotopy)
3. central to the optic chiasm, ganglion cell axons form the optic tract, which is
simply the central continuation of optic chiasm
4. axons (and branches of axons) exit the optic tract and terminate in central
targets in the diencephalon and/or midbrain
5. the principle projection to the visual parts of the cerebral cortex originates in
the LGN and terminates in V1, Brodmann’s Area 17 (also called the “striate
cortex”, for its prominent striation in the human brain), which is located in the
banks of the calcarine fissure on the medial aspect of the occipital lobe
B. retinotopic organization of the visual field projections
1. general principles

2
 Central Visual Pathways

a. the nearest neighbor relationships within each half-retina are

maintained throughout the projections to the LGN and primary visual
cortex; this is termed “visuotopy” or “visual topography”
b. however, each hemisphere (LGN and V1) represents the CONTRALATERAL
visual hemifield
2. anatomical basis in the retina for visuotopy
a. some important conventions (see Figure 12.3A)
a. the point of fixation is in the center of the visual field
b. the vertical meridian projects as a vertical line that passes
through the fovea of each retina
c. similarly, the horizontal meridian projects as a horizontal line
that also passes through the fovea
d. temporal refers to the half of the retina (or visual space) that is
lateral to the fovea (or vertical meridian)
e. nasal refers to the half of the retina (or visual space) that is
medial to the fovea (near the vertical meridian)
b. each retina sees overlapping regions of visual space that includes
portions of both visual hemifields (see Figure 12.3B)
(i) binocular visual field is seen by nasal and temporal parts of
both retinas
(ii) monocular crescents of visual space (far temporal in visual
space) are seen only by the extreme medial portion of the nasal
retina (the nose gets in the way!)
c. the lens inverts and reverses the optical image: the superior part of the
visual field is seen by the inferior part of the retina, and the temporal
half of the visual field is seen by the nasal half of the retina
d. how are the central projections from “corresponding” points in each
retina that see the same position in visual space brought together in the
brain? (see Figure 12.4)
a. axons of ganglion cells in the nasal retina decussate in the optic
chiasm and project to the contralateral hemisphere
b. the axons of ganglion cells in the temporal retina do not cross
and remain ipsilateral
c. the line of decussation in the retina runs through the fovea
3. in the LGN
a. each optic tract terminates in an orderly fashion, so that each LGN
contains an orderly map of the contralateral visual hemifield
b. however, the axons from each retina terminate in distinct layers
4. in V1

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 Central Visual Pathways

a. the projections of the LGN to V1 terminate in proper topographic order

in cortical layer 4 (see Figure 12.5)
b. the fovea is represented in the posterior part of the calcarine sulcus,
with more peripheral parts of the contralateral visual hemifield
represented in progressively more anterior locations
c. the upper visual field is represented in the inferior bank of the calcarine
sulcus, while the lower visual field is represented in its superior bank
d. the representation of the fovea is disproportionately large (like the
“over-representation” of the hand in S1)
e. on the way to V1, the projection of the LGN is called the optic radiation
(see Figure 12.7)
(i) the lateral-inferior part, called Meyer’s loop, “loops” into the
white matter of the temporal lobe before projecting onto the
inferior bank of the calcarine sulcus (terminating in the lingual
gyrus)
(ii) the more medial-superior fibers course through the white
matter of the parietal lobe before projecting onto the superior
bank of the calcarine sulcus (terminating in the cuneus gyrus)
III. Extrastriate Visual Cortex
A. beyond V1 (= “striate cortex”), there are multiple areas in the occipital, parietal and
temporal lobes that process visual information (see Figure 12.16-12.18)
B. these areas are arranged into two broad functional pathways that feed visual
information from V1 into associational cortical areas in the parietal and temporal lobes
(see Figure 12.18):
1. dorsal or lateral parietal pathway: responsible for spatial aspects of vision, such
as the relationships between objects and ourselves and the movements of
objects (including ourselves) through the environment (i.e., “where?”)
2. ventral or inferior temporal pathway: responsible for high-resolution form
vision, color processing and object recognition (i.e., “what?”)

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 Central Visual Pathways

STUDY QUESTIONS
Q1. Where are the cell bodies that grew their axons into the right optic tract?
A. left nasal retina
B. right nasal retina
C. left temporal retina
D. right temporal retina
E. A&D
F. B&C
G. A&B
H. C&D

Q2. There is a female patient who happens to enjoy a hot cup of tea most days at about 4:00 PM.
Her problem is that she frequently spills her tea. The reason she spills her tea is that she does
not appreciate the movement of tea filling her tea cup as she pours it out. She also has great
difficulty judging the movement of traffic when she crosses a street at a crosswalk. Which of the
following best explains her visual impairment?
A. She is blind in her non-dominant eye.
B. She is blind in her dominant eye.
C. She has torn the center of her optic chiasm.
D. She has a lesion in her inferior occipitotemporal association cortex in her non-dominant
hemisphere.
E. She has a lesion in her lateral parieto-occipital associational cortex in her dominant
hemisphere.

5
 Visual Field Deficits

Medical Neuroscience | Tutorial Notes

Visual System: Visual Field Deficits

MAP TO NEUROSCIENCE CORE CONCEPTS1

NCC1. The brain is the body's most complex organ.
NCC3. Genetically determined circuits are the foundation of the nervous system.
NCC8. Fundamental discoveries promote healthy living and treatment of disease.

LEARNING OBJECTIVES
After study of the assigned learning materials, the student will:
1. Describe the distribution of the axons of retinal ganglion cells to major processing centers in the
forebrain and brainstem.
2. Discuss the topographic representation of visual space in the primary visual cortex (V1) and its
anatomical basis in the organization of visual projections.
3. Characterize, using appropriate clinical terms, the visual field deficits associated to damage or
disease along the central visual pathways.

TUTORIAL NARRATIVE

Visual field deficits

A deficit in the visual fields (a region in the visual field of one or both eyes in which there is a loss of
sight) is referred to as a scotoma. You might think that a scotoma would be very obvious to an individual
who has one, and many times they are. But sometimes, especially when it occurs in the periphery, a
scotoma may go unrecognized until the individual has an accident that all too vividly reveals her/his
sensory loss. (Traffic accidents are a common way to uncover such visual field deficits.)
Review the central projections of retinal ganglion cells to targets in the diencephalon and midbrain (see
Figure 12.12 for gross overview and tutorial: “Visual System—Central Visual Pathways”).
On the right side of Figure 12.6, you will see examples of different types of visual field deficits. In each
case, the regions of the visual field of each eye that are affected are shown in black. That is, the part of
the visual field that is not visible in that eye is blacked out. Visual field diagrams are always done for
each eye individually. Some deficits would not be easy to demonstrate if both eyes were open during
the testing. On the left of the figure, lines are drawn through parts of the visual pathways to indicate
locations that could be damaged to give each of the illustrated patterns of deficits.

1
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 Visual Field Deficits

Some rather cumbersome names are used to refer to particular patterns of visual field deficits. Anopsia
(also spelled anopia) simply means loss of sight in one or both eyes. Hemianopsia indicates loss of sight
in one half of the visual field. Quadrantanopsia is a loss of sight in one quadrant of the visual field.
Bitemporal hemianopsia is a loss of sight in the right visual field of the right eye and the left visual field
of the left eye. It is also called heteronymous hemianopsia because the affected regions of the visual
fields in the two eyes are not congruent. When the affected regions of the visual fields of both eyes
overlap (i.e., loss of vision in the left or right visual field of both eyes), the deficit is called homonymous.
A patient could be described as having a homonymous hemianopsia or a homonymous
quadrantanopsia, etc.
Widespread loss of vision without damage to the most central part of the visual field representation is
called macular sparing. Macular sparing is a phenomenon often associated with lesions in the visual
cortex but it can be found with lesions along the length of the visual pathways.
Consider the visual field deficits shown in Figure 12.6 and identify each by the proper clinical term (or
combination of terms) highlighted on this page in bold font. You should be able to relate this figure back
to previous figures on visuotopy and explain why each visual field deficit is associated with damage to
the particular structure along the visual pathway from retina to visual cortex.

STUDY QUESTIONS
Q1. Patient 1. A patient complains of bumping into objects on the right, especially objects such as
chairs and tables that are at waist height or below. You suspect a visual field deficit involving
which structure(s)?
A. lesion in the left eye or left optic nerve
B. lesion in the right eye or right optic nerve
C. lesion in the optic chiasm
D. lesion in the left Meyer’s loop
E. lesion in the right Meyer’s loop
F. lesion in the left parietal white matter
G. lesion in the right parietal white matter
H. lesion in the left cuneus gyrus
I. lesion in the right cuneus gyrus
J. lesion in the left lingual gyrus
K. lesion in the right lingual gyrus

Q1. Patient 2. A patient undergoes neurosurgery to remove an operable tumor (an early stage
glioblastoma, which arises in white matter) from the right temporal lobe. Upon recovery in the
acute care setting, the patient’s caregivers discover that when resting in bed she doesn’t readily
notice visitors approaching from her left. What visual structure may have been injured in this
surgical procedure?
A. lesion in the left eye or left optic nerve
B. lesion in the right eye or right optic nerve
C. lesion in the optic chiasm
D. lesion in the left Meyer’s loop

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 Visual Field Deficits

E. lesion in the right Meyer’s loop

F. lesion in the left parietal white matter
G. lesion in the right parietal white matter
H. lesion in the left cuneus gyrus
I. lesion in the right cuneus gyrus
J. lesion in the left lingual gyrus
K. lesion in the right lingual gyrus

3
 Pupillary Light Reflex

Medical Neuroscience | Tutorial Notes

Visual System: Pupillary Light Reflex

MAP TO NEUROSCIENCE CORE CONCEPTS1

NCC1. The brain is the body's most complex organ.
NCC3. Genetically determined circuits are the foundation of the nervous system.

LEARNING OBJECTIVES
After study of the assigned learning materials, the student will:
1. Describe the distribution of the axons of retinal ganglion cells to major processing centers in the
forebrain and brainstem.
2. Discuss the neuroanatomical basis for the pupillary light reflex.

TUTORIAL OUTLINE

I. Overview of Central Visual Pathways

A. central projections of the retina arise from retinal ganglion cells
B. among the targets of these central projections are a set of nuclei just anterior to the
tectum of the midbrain, in a transitional region between the diencephalon and the
mesencephalon called the pretectum (see Figure 12.12 for gross overview and )
1. pretectum: coordinates the pupillary light reflex (see Figure 12.2)
a. afferent (sensory) limb
i. inputs reach the pretectal nuclei from the ipsilateral optic tract
ii. thus, each side of the pretectum receives input from both eyes
b. efferent (motor limb)
i. the pretectal nuclei send projections bilaterally to the Edinger-
Westphal nuclei
ii. parasympathetic, preganglionic outputs leave the brainstem
through the oculomotor nerve and govern the activity of
constrictor muscles in the iris (pupillary constriction) via
ganglionic input from the ciliary ganglion

1
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 Pupillary Light Reflex

iii. pupillary dilation is under the control of the sympathetic

division of the visceral motor system, with preganglionic
neurons in the upper thoracic spinal cord (intermediolateral cell
column)
2. pretectum is also involved in coordinating the activities of the preganglionic
neurons that innervate the ciliary muscles and allow for accommodation
(changing the shape of the lens)

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 Pupillary Light Reflex

STUDY QUESTIONS
Q1. Patient 1. During a physical exam, you shine a light into a patient’s left eye and you note that
both pupils react only sluggishly to light. You stimulate the right eye and you find a brisk
constriction of both pupils. From this information alone, what sort of neurological problem
might you suspect?
A. lesion in the left eye or left optic nerve
B. lesion in the right eye or right optic nerve
C. lesion in the left optic tract
D. lesion in the right optic tract
E. lesion in the left Edinger-Westphal nucleus or left oculomotor nerve
F. lesion in the right Edinger-Westphal nucleus or right oculomotor nerve
G. insufficient sympathetic tone to the left iris.
H. insufficient sympathetic tone to the right iris.

Q2. Patient 2. A patient has come to you complaining of double vision. His left eye fails to adduct
when he makes eye movements to the right. His left eyelid droops (ptosis) and the pupil in his
left eye is larger than the pupil in the right. The pupil in the left eye does not react to light nor
does it respond when light is shown in the right eye. How would you explain this deficit in the
pupillary light reflex?
A. lesion in the left eye or left optic nerve
B. lesion in the right eye or right optic nerve
C. lesion in the left optic tract
D. lesion in the right optic tract
E. lesion in the left Edinger-Westphal nucleus or left oculomotor nerve
F. lesion in the right Edinger-Westphal nucleus or right oculomotor nerve
G. insufficient sympathetic tone to the left iris.
H. insufficient sympathetic tone to the right iris.

Q3. Patient 3. A third patient comes to see you with ptosis of his left eye. You examine his eye
movements and these seem normal. Then you notice that the pupil in his left eye is measurably
smaller than that of his right eye. How do you account for the symptoms in this case?
A. lesion in the left eye or left optic nerve
B. lesion in the right eye or right optic nerve
C. lesion in the left optic tract
D. lesion in the right optic tract
E. lesion in the left Edinger-Westphal nucleus or left oculomotor nerve
F. lesion in the right Edinger-Westphal nucleus or right oculomotor nerve
G. insufficient sympathetic tone to the left iris.
H. insufficient sympathetic tone to the right iris.

3
 Auditory System—Peripheral Mechanisms

Medical Neuroscience | Tutorial Notes

Auditory System—Peripheral Mechanisms

MAP TO NEUROSCIENCE CORE CONCEPTS1

NCC1. The brain is the body's most complex organ.
NCC3. Genetically determined circuits are the foundation of the nervous system.
NCC6. The brain makes it possible to communicate knowledge through language.
NCC7. The human brain endows us with a natural curiosity to understand how the world works.

LEARNING OBJECTIVES
After study of the assigned learning materials, the student will:
1. Describe the biomechanics of sensory transduction in the middle and inner ear, including the
tonotopy of the basilar membrane.
2. Characterize the neurophysiology of sensory transduction in auditory hair cells.

TUTORIAL OUTLINE

I. Introduction to the Auditory System

A. overview of auditory function: the auditory system transduces sound waves into distinct
patterns of neural activity that are then integrated with other sensations and
motivations to guide behavior
1. sound waves are collected and amplified by physical structures in the external
and middle ear for transfer to neural elements in the inner ear
2. the biomechanical properties of the inner ear decompose complex sound waves
into sinusoidal components, so that component frequencies, their amplitude,
and their phase can be encoded in the firing of the receptor cells
3. in the inner ear and throughout central processing stations, tonotopy is
preserved; i.e., the systematic representation of sound frequency
4. in the brainstem, the auditory information is first processed and divided into
several parallel pathways, some of which compare the signals derived from the
two ears, a process that allows for the localization of sounds in space
5. in addition to local processing of auditory signals, brainstem centers relay
information to the midbrain, which in turn projects to the auditory thalamus

1
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 Auditory System—Peripheral Mechanisms

6. the auditory cortex then receives input from the thalamus and processes more
complex aspects of sounds, such as those related to human speech
II. Sound
A. comes from spherical pressure waves generated by vibrating air molecules (see Figure
13.12) that can be characterized by their amplitude (loudness), frequency (pitch) and
phase (temporal displacement) (see Figure 13.2)
B. most natural sounds (human speech, for example) are acoustically complex
C. humans can detect sound in the frequency range of 20 Hz to 20 kHz
III. The ear
A. external ear (pinna, concha, auditory meatus) (see Figure 13.3)
1. gathers sound energy and focuses it on the tympanic membrane (ear drum)
2. filters different sound frequencies to provide cues about sound localization
B. middle ear (tympanic membrane, ossicles)
1. transmit acoustic energy from air to the inner ear
2. amplifies the pressure of acoustic energy some 200-fold
C. inner ear (cochlea, auditory nerve)
1. two-fold function:
a. biomechanical: decompose complex acoustic energy into component
sinusoidal waveforms
b. neural (sensory transduction): transduce this mechanical energy into
neural signals that are then communicated to the brain
2. cochlea (Greek, cochlos = snail)
a. basic anatomy (see Figure 13.4)
(i) small, coiled structure surrounded by bone
(ii) bisected by the cochlear partition into two, large fluid filled
channels (scala vestibuli, scala tympani)
(iii) the cochlear partition contains the organ of corti, which
consists of the basilar and tectorial membranes
(iv) the basilar membrane supports inner and outer hair cells; the
inner hair cells are the sensory receptor cells of the cochlea
(v) the cochlear partition contains a smaller, fluid filled channel
(scala media), which is important for maintaining the proper
ionic environment for neural signaling
(vi) the cochlear partition terminates before the apical end of the
cochlea, allowing for continuity between the scala vestibuli and
scala tympani (at the helicotrema)

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 Auditory System—Peripheral Mechanisms

b. functional overview
(i) pressure transmitted by the ossicles of the middle ear causes
the oval window to bulge inward
(ii) this pressure is conducted throughout the fluid of the scala
vestibuli (called perilymph), around the helicotrema and into
the scala tympani, and is relieved by the outward bulging of the
round window
(iii) passage of pressure throughout the channels of the cochlea sets
up vibrations in the basilar membrane (see Figure 13.5)
(iv) movements of the basilar membrane deform the ends of the
inner hair cells leading to the transduction of mechanical energy
into neural impulses (see Figure 13.6)
c. basilar membrane
(i) frequency tuning (refer back to Figure 13.5)
- the membrane is stiffer, thicker and narrower at the
base of the cochlea and wider, thinner and more
flexible at the apex of the cochlea
- thus, the base is tuned for (responds best to) high
frequencies and apex is tuned for low frequencies
- complex sounds cause vibrations of different parts of
the basilar membrane
- tuning is sharpened by an active process involving the
outer hair cells
(ii) sensory transduction (see Figure 13.7-13.10)
- the stereocilia of hair cells protrude into the scala
media, which contains endolymph – a solution that
contains high concentrations of K+
- vibration of the basilar membrane causes a shearing
motion between the basilar and tectorial membranes
- motion bends the stereocilia that protrude from the
apical ends of the inner hairs cells
- deformation of the stereocilia toward the longest
stereocilia leads to inward flow of current through K+
channels and depolarization of the hair cell membrane
- depolarized hair cells release more neurotransmitter on
afferent endings, resulting in an increase in action
potential firing in the auditory nerve
- deformation of the stereocilia away from the longest
stereocilia leads to closure of K+ channels and
hyperpolarization of the hair cell membrane

3
 Auditory System—Peripheral Mechanisms

- hyperpolarized hair cells release less neurotransmitter

on afferent endings, resulting in an decrease in action
potential firing in the auditory nerve
(iii) hearing loss (see Boxes 13A & 13C)
3. for an excellent review of the anatomy and physiology of these peripheral
components of the auditory system, see the animation on the textbook’s
companion website [click here]
4. for an more aesthetically satisfying experience (featuring Bach’s Toccata &
Fugue in D minor), see also this fantastic animation produced by James Huspeth
(Rockefeller University), one of the world’s leading auditory neurophysiologists
[click here]
5. sensory coding in the auditory nerve (see Figures 13.9 & 13.11)
a. temporal code: hair cell potentials and action potentials in the auditory
nerve can follow an acoustical stimulus up to about 3 kHz
b. “labeled-line” code: preserves information about frequency since the
afferent fibers that innervate different parts of the basilar membrane
inherit their tuning (from the basilar membrane)

4
 Auditory System—Peripheral Mechanisms

STUDY QUESTIONS
Q1. Which of the following is the primary function of the three bones in the middle ear?
A. Selective transmission of high-frequency sounds
B. Selective transmission of low-frequency sounds
C. Amplification of sound pressure waves to increase auditory sensitivity
D. Dampening sound pressure waves to prevent damage to the ear
E. Facilitation of fluid drainage from the Eustachian tube

Q2. Which of the following statements about sensory transduction by hair cells is most accurate?
A. Bending of the cilia toward the shortest cilium produces depolarization.
B. Bending of the cilia toward the longest cilium produces hyperpolarization.
C. Neurotransmitter is released by hair cells when the calcium that rushes into the cilia
reaches the active zone at the base of the hair cells.
D. The firing of action potentials in second-order sensory neurons can be either up- or
down-regulated, depending on the direction in which the bundle of cilia (of the afferent
hair cell) is bent.
E. Hair cells are postsynaptic to second-order sensory neurons.

Q3. What explains the tonotopy that is present in the auditory division of CN VIII?
A. The amount of myelin wrapping any given axon: the more myelin, the higher the pitch
encoded by the axon.
B. The location of the cell body in the spiral ganglion: the closer to the center of spiral, the
lower the pitch encoded by the axon.
C. The location of where the peripheral process receives contact from hair cells along the
basilar membrane.
D. The average rate of action potential generation: the higher the average rate of action
potential generation, the higher the pitch encoded by the axon.
E. The number of AMPA receptors in the postsynaptic process: the more AMPA receptors,
the higher the pitch encoded by the axon.

5
 Auditory System—Central Processing

Medical Neuroscience | Tutorial Notes

Auditory System—Central Processing

MAP TO NEUROSCIENCE CORE CONCEPTS1

NCC1. The brain is the body's most complex organ.
NCC3. Genetically determined circuits are the foundation of the nervous system.
NCC6. The brain makes it possible to communicate knowledge through language.
NCC7. The human brain endows us with a natural curiosity to understand how the world works.

LEARNING OBJECTIVES
After study of the assigned learning materials, the student will:
1. Identify the neural mechanisms for localizing sounds in space.
2. Discuss the organization of the auditory cortex.

TUTORIAL OUTLINE

I. Central processing of auditory information

A. subcortical pathways (see Figure 13.122)
1. first order neurons: spiral ganglion cells
a. peripheral process innervates inner hair cells
b. central process enters the pontine-medullary junction and bifurcates to
innervate the cochlear nucleus
2. second order neurons: cells in the cochlear nucleus that project to multiple
targets on both sides of the brainstem
a. (contralateral) nucleus of the lateral lemniscus in the upper pons:
involved in detecting presence and temporal properties of sound from
one ear (a monaural pathway)
a. (bilateral) superior olivary complex in the mid-pons: different divisions
of this complex are involved in localizing the sources of sounds in
auditory space
(i) medial superior olive (MSO) (see Figure 13.13): localizes low
frequency sounds based on interaural timing differences

1
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 Auditory System—Central Processing

(ii) lateral superior olive (LSO) (see Figure 13.14): localizes sound
based on interaural intensity differences
3. inferior colliculus
a. all lower auditory projections converge on the inferior colliculus
b. here, for the first time in the auditory system, a complete map of
auditory space is computed in the inferior colliculus
4. auditory thalamus
a. inferior colliculus projects to the medial geniculate complex
b. cells in the MGC are sensitive to particular combinations of sounds with
distinct spectral and temporal characteristics
B. auditory cortex
a. target of the MGC located on the superior aspect of the temporal lobe
b. contains several subdivisions (see Figure 13.15)
i. “core” area or primary auditory cortex that receives highly tonotopic input
from the MGC; also maps binaural interactions
ii. “belt” of additional, higher-order auditory areas
c. asymmetry in structure and function
i. the posterior portion of the auditory belt contains Wernicke’s area, a
division of the auditory cortex that is specialized (in humans) for
comprehending speech
ii. for most people (>99% of right-handers and >90% left-handers), functional
Wernicke’s area is in the left hemisphere
iii. there is a structural asymmetry associated with this functional asymmetry:
the planum temporale (the superior plane of the temporal lobe)
- the left planum temporale is larger in most humans than the right
- the degree of asymmetry is associated with perfect pitch abilities
(greater asymmetry in people with perfect pitch)
iv. activation of the right hemisphere is typically greater in the left when
listening to music, compared to listening to speech and environmental
sounds (see Box 13E)

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 Auditory System—Central Processing

STUDY QUESTIONS
Q1. Which of the following most depends upon the utilization of bilateral auditory information?
A. frequency discrimination
B. sound localization
C. distinguishing pitch from timbre
D. encoding of speech sounds
E. detection of very faint sounds

Q2. Which auditory structure first displays pronounced selectivity for specific combinations of sound
frequencies in the auditory pathway?
A. cochlear nucleus
B. lateral superior olive
C. medial superior olive
D. nuclei of the lateral lemniscus
E. inferior colliculus
F. medial geniculate complex
G. auditory cortex

3
 Vestibular System—Peripheral Mechanisms

Medical Neuroscience | Tutorial Notes

Vestibular System—Peripheral Mechanisms

MAP TO NEUROSCIENCE CORE CONCEPTS1

NCC1. The brain is the body's most complex organ.
NCC3. Genetically determined circuits are the foundation of the nervous system.

LEARNING OBJECTIVES
After study of the assigned learning materials, the student will:
1. Describe the anatomy of the vestibular labyrinth.
2. Describe the biomechanics of sensory transduction in the vestibular labyrinth, including the
biophysics of hair cell sensory transduction.

TUTORIAL OUTLINE

I. Overview
A. vestibular labyrinth is an extension of the inner ear designed to sense the motions that
arise from head movements and the inertial effects due to gravity (see Box 14A2)
1. static head position and linear accelerations of the head are sensed by hair cells
in the otolith organs
2. rotational accelerations are sensed by hair cells in the semicircular canals
A. vestibular signals are relayed to integrative centers in the brainstem and cerebellum,
where it is used to adjusted postural reflexes and eye movements
B. vestibular signals also reach parts of the parietal cortex, where our normal sense of
orientation in three-dimensional space is constructed and (should pathology present) a
sense of dizziness with abnormal vestibular stimulation

II. Peripheral vestibular systems

A. anatomy of the vestibular labyrinth (see Figure 14.1)
1. set of interconnected canals that arise from the same embryological precursor
(otic placode) as the cochlea
2. canals are filled with endolymph (high K+ / low Na+) and surrounded by
perilymph (low K+ / high Na+)
1
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 Vestibular System—Peripheral Mechanisms

3. two classes of sensory structures in each side of the head:

a. two otolith organs: the utricle and sacculus
b. three semicircular canals arranged orthogonally to one another
4. within each sensory structure, there are hair cells that transduce motion signals
into neural impulses
5. hair cells are innervated by the vestibular division of cranial nerve VIII (cell
bodies reside in Scarpa’s ganglia)
B. vestibular hair cells
1. sensory transduction (see Figure 13.8, 14.2 A,B)
a. deformation of stereocilia toward the largest stereocilium leads to
depolarization and increased release of neurotransmitter on peripheral
endings of afferent fibers
b. deformation away from the largest stereocilium leads to
hyperpolarization and decreased release of neurotransmitter
2. orientation of hair cells in sensory structures (see Figure 14.2C)
a. common principle: hair cells (stereocilia) are arranged in parallel to the
direction of biomechanical motion within the sensory structure
b. semicircular canals
(i) hair cells in ampullae are arranged in one orientation so that
motion of endolymph in one direction will depolarize hair cells,
and motion in the opposite direction will hyperpolarize
c. otolith organs
(i) hair cells in the maculae of the utricle and sacculus are arranged
into two populations with opposing orientations along an axis of
mirror symmetry
(ii) motion in one direction will depolarize one subpopulation of
hair cells and hyperpolarize the other
C. mechanism of otolith organ function
1. macula: sensory epithelium of the otolith organs
a. consists of a hair cells and supporting cells, and an overlying gelatinous
layer (the otolithic membrane) upon which are embedded crystals of
calcium carbonate, called otoconia
b. the hair cells protrude into this gelatinous layer, which is heavier than
the surrounding epithelium and fluids
2. when the head is tilted, gravity causes the gelatinous membrane to shift relative
to the underlying epithelium; this displaces the hair cell stereocilium and leads
to tonic depolarization and hyperpolarization (see Figure 14.5)

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 Vestibular System—Peripheral Mechanisms

3. with linear acceleration, the same sort of shearing motion is induced because
the heavier otolithic membrane transiently lags behind the sensory epithelium;
this leads to phasic depolarization and hyperpolarization of the hair cells
4. the utricular maculae are orientated more or less horizontally and, therefore,
sense movements of the head in the horizontal plane
5. the saccular maculae are oriented roughly vertically and sense up and down
movements of the head, as well as head tilts in the sagittal plane
D. mechanism of semicircular canal function
1. ampulla
a. bulbous expansion at the base of the semicircular canals that contains
the sensory epithelium (called the crista) and an overlying gelatinous
mass (called the cupula) into which the stereocilium of the hair cells
protrude (see Figure 14.7)
b. the cupula creates a barrier for the flow of endolymph around the
semicircular canal
2. when the head is rotated in the plane of the semicircular canal, the inertia of
the endolymph produces a transient force that distends the cupulla away from
the direction of rotation (see Figure 14.8A,B)
3. distension of the cupulla deflects the stereocilia of the hairs cells, which leads to
depolarization or hyperpolarization of the hair cells within any given crista
4. semicircular canals are paired on the two sides of the head (see Figure 14.8C):
a. left horizontal and right horizontal
b. left anterior (superior) and right posterior
c. left posterior and right anterior (superior)
5. rotation of the head in one direction will depolarize the hair cells in one
member of the pair and hyperpolarize the hair cells in the other (see Box 14C)
a. thus, pairs of horizontal canals function in a “push-pull” manner
b. the central processing of vestibular afferents reflects the balance of
activity arising from the paired semicircular canals

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 Vestibular System—Peripheral Mechanisms

STUDY QUESTIONS
Q1. When looking up into the night sky (while standing), which of the following events happened
deep in the vestibular labyrinth?
A. The superior (anterior) semicircular canals on both sides of your head were phasically
activated during the backward tilt of your head.
B. The horizontal semicircular canals on both sides of your head were phasically activated
during the backward tilt of your head.
C. The posterior semicircular canals on both sides of your head were phasically activated
during the backward tilt of your head.
D. All of the hair cells in the utricles on both sides of your head were depolarized while you
maintained your head in a backward tilt.
E. About half of the hair cells in the sacculus on both sides of your head were depolarized
while you maintained your head in a backward tilt.

Q2. When riding a “merry-go-round” (that rotates in the counterclockwise direction), which of the
following events happened deep in the vestibular labyrinth?
A. The superior (anterior) semicircular canals on both sides of your head were phasically
activated during the acceleration of the ride.
B. The posterior semicircular canals on both sides of your head were phasically activated
during the acceleration of the ride.
C. The left horizontal semicircular canal was activated.
D. The right horizontal semicircular canal was activated.
E. All of the hair cells in the utricles on both sides of your head were depolarized while the ride
was at full operating speed.

4
 Vestibular System—Central Processing

Medical Neuroscience | Tutorial Notes

Vestibular System—Central Processing

MAP TO NEUROSCIENCE CORE CONCEPTS1

NCC1. The brain is the body's most complex organ.
NCC3. Genetically determined circuits are the foundation of the nervous system.

LEARNING OBJECTIVES
After study of the assigned learning materials, the student will:
1. Discuss the neuroanatomy and function of the vestibulo-ocular reflex.
2. Characterize the contributions of vestibulo-spinal projections in postural control.
3. Discuss the contributions of vestibular sensation to proprioception.

TUTORIAL OUTLINE

I. Overview
A. vestibular labyrinth is an extension of the inner ear designed to sense the motions that
arise from head movements and the inertial effects due to gravity (see Box 14A2)
1. static position and linear accelerations are sensed by hair cells in the otolith
organs
2. rotational accelerations are sensed by hair cells in the semicircular canals
B. vestibular signals are relayed to integrative centers in the brainstem and cerebellum,
where it is used to adjusted postural reflexes and eye movements
C. vestibular signals also reach parts of the parietal cortex, where our normal sense of
orientation in three-dimensional space is constructed and (should pathology present) a
sense of dizziness with abnormal vestibular stimulation

II. Central vestibular processing

A. central processes of ganglion cells project via the vestibular division of the eighth cranial
nerve to vestibular nuclei in the rostral medulla and caudal pons, and directly to the
“vestibulocerebellum” (flocculonodular lobe of the cerebellum)
B. one major function of the vestibular nuclei is to coordinate movements of the eyes and
head to allow for stable visual fixation during head or whole body movements
1
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 Vestibular System—Central Processing

C. vestibulo-ocular reflex
1. rotational movements of the head induce eye movements opposite to the
direction of rotation, thus allowing maintained visual fixation of both eyes
2. pathway (see Figure 14.10)
a. input from the horizontal canals reaches the vestibular nuclei on the
two sides of the medulla/pons
b. each vestibular nucleus in turn sends a excitatory projections to the
contralateral abducens nucleus
c. the abducens nucleus directly innervates the ipsilateral lateral rectus
muscle, which pulls that eye toward the lateral side (i.e., abduction)
d. other cells in the abducens nucleus cross the midline again and project
to the opposite oculomotor nucleus, which innervates the ipsilateral
medial rectus causing that eye to turn toward the midline (i.e.,
adduction)
e. to facilitate this excitatory action, there are also inhibitory projections
from the vestibular nuclei to the ipsilateral abducens nucleus
f. this inhibitory projection turns off the excitatory output of the cranial
nerve nuclei (opposite abducens and oculomotor nuclei) that drive the
antagonistic muscles
3. vestibular nystagmus
a. nystagmus = rhythmic form of reflexive eye movements composed of
slow component in one direction interrupted repeatedly by fast
saccadic-like movements in the opposite direction
b. vestibular nystagmus is normally driven by persistent rotation of the
head; the slow component is driven by the vestibulo-ocular reflex and
the fast (“saccadic”, see below) component that resets eye position
c. the balance between the activities of VIII n. afferents that arise from the
functional pairs of semicircular canals determines the type and direction
of nystagmus expressed
d. pathological alteration in the balance of activity between the two sides
can cause the expression of nystagmus (and other vestibular-evoked
signs and symptoms) under conditions that normally would not induce
this ocular motor behavior
D. postural reflexes
1. another major function of the vestibular nuclei is to make reflexive adjustments
of posture that compensate for movements of the head
2. descending projections from the vestibular nuclei reach the medial aspect of the
ventral horn of the spinal cord via medial and lateral vestibulospinal pathways
(see Figure 14.11)

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 Vestibular System—Central Processing

a. medial vestibulospinal projection to the upper cervical cord that

regulates head and neck position
b. “lateral” vestibulospinal projection to motor neurons in the medial
ventral horn that excite extensor muscles in the trunk and limbs; this
pathway mediates balance and maintenance of an upright posture
E. vestibular perception
1. vestibular signals also ascend to the cerebral cortex where they reach conscious
perception (see Figure 14.12)
2. vestibular nuclei sends axons bilaterally that synapse in the ventral posterior
complex of the thalamus on both sides of the brain
3. these vestibular-receptive neurons in the thalamus project to the lateral part of
the somatic sensory cortex (specifically, Brodmann’s Area 3a and a part of
Brodmann’s Area 2), near the face representation; these same areas also
represent other somatic sensory modalities, so it is not clear if there is a
dedicated “primary vestibular cortex”
4. other thalamic projections to parietal area 5 also contribute and, together with
higher-order connections in parietal cortex, integrate somatic sensory
proprioception, visual information about movement, and vestibular
proprioception to construct a body schema relative to 3D space
F. other vestibular connections
1. vestibular nuclei also receive input from most other sensory modalities in order
to guide orienting movements of the head toward relevant stimuli
2. vestibular nuclei receive input from the cerebellum (cortex and deep nuclei)
that modulate vestibular output to ocular motor nuclei and spinal cord

3. vestibular output is also directed toward certain autonomic centers in the

reticular formation of the medulla, which mediate nausea sensations and
influence states of consciousness

STUDY QUESTION
Stare straight ahead at some frontal fixation target. Now turn your head to the right without breaking
fixation. What just happened?
A. The left horizontal semicircular canal was phasically activated during the rightward turn of
your head.
B. The motor neurons in your right oculomotor nucleus that innervate the right medial rectus
muscle just increased their firing rate.
C. The motor neurons in your right abducens nucleus that innervate the right lateral rectus
muscle just increased their firing rate.
D. An inhibitory neuron projecting from the left abducens nucleus to the right oculomotor
nucleus just suppressed the activation of the right lateral rectus muscle
E. Your eyes rotated in the orbits to the right along with your head turn.

3
 Chemical Senses—Overview & Olfaction

Medical Neuroscience | Tutorial Notes

Chemical Senses—Overview & Olfaction

MAP TO NEUROSCIENCE CORE CONCEPTS1

NCC1. The brain is the body's most complex organ.
NCC3. Genetically determined circuits are the foundation of the nervous system.

LEARNING OBJECTIVES
After study of the assigned learning materials, the student will:
1. Characterize the peripheral and central organization of the olfactory system.
2. Discuss sensory transduction in olfactory receptor cells.
3. Describe information coding in the olfactory system.

TUTORIAL OUTLINE

I. Overview of the chemical senses

A. special sensory systems in the face—in the nose, mouth and eyes—are capable of
detecting minute quantities of chemical molecules in the environment
1. airborne molecules give rise to:
a. olfactory (smell) sensations via the olfactory system; and
b. noxious (nociceptive) sensations in the oral and nasal cavities, and in
the corneas and conjunctiva of the eyes via the trigeminal
chemosensory system
2. ingested (mostly water-soluble) molecules give rise to gustatory (taste)
sensations via the gustatory system
B. the chemical senses provide a wealth of information across multiple domains of human
behavior; they provide important cues that are relevant to:
1. nutrition (palatable and desirable foods and drink; unpalatable or potentially
harmful foods and drink)
2. physiological functions (visceral motor activities, reproductive cycles, infant-
paternal behavior)
3. social interactions (self and others)

1
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 Chemical Senses—Overview & Olfaction

4. safety (harmful volatile chemicals in the environment)

5. even hedonic rewards (attractive perfumes, flower scents, pleasurable food
tastes, human pheromones?)
C. thus, the chemical senses can be powerful sources of motivation that can profoundly
influence human (and animal) behavior

II. Organization of the olfactory system

A. anatomical overview (see Figure 15.12)
1. airborne molecules, called odorants, enter the nasal cavity (passively or during
active sniffing) where they diffuse through a layer of mucus and interact with
olfactory receptor neurons in the olfactory epithelium
2. the axons that arise from the receptors cells project through the cribriform plate
and synapse in the olfactory bulb, which is a telencephalic structure connected
to the olfactory cortex by the lateral olfactory tract (despite its appearance, this
is not a nerve!)
3. the projections neurons of the olfactory bulb, called mitral cells, send their
axons to the olfactory cortex, which is comprised of a large set of cortical areas
in the ventral-medial surface of the forebrain, including:
a. piriform cortex (in junction of temporal lobe and posterior frontal lobe)
b. olfactory tubercle (actually, part of the ventral striatum)
c. cortical divisions of the amygdala
d. entorhinal cortex (part of the hippocampal formation in
parahippocampal gyrus)
4. different parts of the olfactory cortex are extensively interconnected and many
parts project to other cortical and subcortical regions, including the thalamus,
hypothalamus and the orbital-medial prefrontal cortex
5. two exceptional aspects of organization worth noting:
a. the olfactory system is the one sensory system that does not relay
information through the thalamus before reaching the cortex
b. the olfactory cortex has no (known) map of the sensory environment or
the sensory epithelium
B. sensory transduction
1. at the apical end of olfactory receptor neurons, there are olfactory cilia that
extend into a thick layer of mucus (see Figure 15.7A)
2. odorants bind to specific molecular receptors located in the plasma membrane
of the cilia
3. a sequence of molecular reactions lead to the depolarization of the olfactory
receptor neuron and the generation of a receptor potential (see Figure 15.11)
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 Chemical Senses—Overview & Olfaction

a. odorant binding activates an olfactory-specific G-protein (Golf, a member

of the 7-transmembrane, G-protein linked receptor family)
b. activated G-proteins, in turn, activate an olfactory-specific adenylate
cyclase, which increases the production of cAMP
c. cAMP opens cation-selective ion channels that allow influx of Na+ and
Ca++; this leads to the depolarization of the receptor neuron
d. activation of a Ca++-gated, Cl- conductance allows for the efflux of Cl- and
further adds to the depolarization
e. if threshold is reached, then action potentials are generated at the base
of the receptor neuron and transmitted to the olfactory bulb via the
olfactory nerve (cranial nerve I)
4. olfactory receptor neurons adapt in the continued presence of an odorant (a
familiar experience to all)
a. Ca++ binds to calmodulin (CAM) and the Ca++-CAM complex interacts
with the cation-selective channel and reduces its sensitivity to cAMP
b. removal of Ca++ via the Na+/Ca++ exchanger reduces the intracellular
concentration of Ca++ ; this reduces the receptor potential
C. olfactory coding & perception
1. odorant-receptor interactions
a. humans are sensitive to odorants in the nanomolar to millimolar
concentration ranges
i. small changes in molecular structure can lead to major changes
in perception (e.g., D-carvone smells like rye, but L-carvone
smells like spearmint)
ii. the quality of an odor evoked by an odorant depends on its
concentration (e.g., low concentrations of indole smell like a
floral bouquet, but high concentrations smell putrid)
iii. most natural odors are a complex mixture of a least several
odorants at different concentrations
b. some individuals lack certain genes that encode particular olfactory
receptors and are anosmic for certain odorants
2. the “logic” of olfactory coding
a. different odors activate molecularly and spatially distinct subsets of
olfactory receptor neurons (ORNs) in the olfactory epithelium
i. different olfactory receptor genes are expressed in subsets of
ORNs that are distributed in bilaterally symmetrical zones of the
olfactory epithelium
ii. however, most ORNs expresses only one allele of about 400
olfactory receptor genes

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 Chemical Senses—Overview & Olfaction

- some olfactory receptor proteins are activated by

just one type of odorant molecule
- but others are activated by a number of different
odorant molecules
- thus, there is a “combinatorial code” (rather than a
labeled-line code) of olfactory receptors, with
receptor encoding the molecular shape of odorants
b. convergence of ORN axons in the olfactory bulb
i. the principle cells of the olfactory bulb, called mitral cells, send
dendrites into complexes of synapses (neuropil) called
glomeruli (see Figure 15.14D)
ii. each glomerulus receives input from about 25,000 ORNs, with
each of these ORNs expressing the same olfactory receptor
protein!
- this remarkable convergence may maximize the
fidelity and sensitivity of odorant detection
iii. all the ORNs that express the same olfactory receptor allele
converge onto a small subset of bilaterally symmetrical
glomeruli in the two olfactory bulbs
iv. each glomerulus also contains synaptic connections of
additional cell types in the olfactory bulb, including tufted cells,
periglomerular cells and granule cells
- granule cells are thought to mediate lateral
inhibitory connections across mitral cells
- granule cells may participate in plasticity of neural
circuits in the olfactory bulb
c. to solve the problem of coding complex odors, the olfactory bulb
employs a sparse coding mechanism, with a relatively small number of
glomeruli activated by a subset of dominant molecular shapes that may
be present in complex odors
d. temporal coding in the olfactory cortex
i. the convergence of molecular information in the olfactory bulb
is apparently lost in the projections of mitral cells to the
olfactory cortex
- a single odorant produces activation in neurons that
are broadly distributed across the olfactory cortex
- mitral cells that receive input from the same
glomerulus make synaptic connections with
neurons throughout a large extent of the olfactory
cortex

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 Chemical Senses—Overview & Olfaction

ii. thus, in the absence of an obvious spatial code and a map of the
olfactory epithelium in the olfactory cortex, olfactory
perception is likely based upon a temporal code
iii. central olfactory structures oscillate (i.e., firing nearly
synchronous patterns of action potentials) when particular
odorants are presented
3. physiological effects of odorants
a. olfactory information reaches a variety of integrative centers in the
forebrain that allow olfactory cues to influence cognitive, visceral,
emotional and homeostatic behaviors
i. the piriform cortex sends input to the orbital-medial prefrontal
cortex (see Figure 15.1C), where multimodal input related to
complex stimuli—such as food—becomes integrated
ii. the piriform cortex also projects to the mediodorsal thalamic
nucleus, which projects to the prefrontal cortex, including the
dorsal-lateral sector where olfactory signals may be used to
guide working memory (e.g., search or tracking behavior)
iii. olfactory projections to the entorhinal cortex (parahippocampal
gyrus) are implicated in olfactory based memory acquisition and
memory recall
b. in many species (possible including humans), species-specific odorants
called pheromones play an important role in influencing social
interactions and reproductive behavior (although humans lack a
vomeronasal organ, which tranduces pheromone signals in most
mammals)
c. the ability to detect and discriminate odors normally decreases with age
(see Figure 15.5B)
d. the ability to detect and discriminate odors may be lost following
traumatic head injury, if the axons of CN I are severed by movement of
the brain relative to the cribiform plate (see Figure 15.1A-B)
i. however, some olfactory function may recover with the
regrowth of ORN axons to the olfactory bulb
ii. ORNs normally undergo a cycle of degeneration and
replacement by new ORNS that differentiate from a population
of neuronal stem cells from among the basal cells in the
olfactory epithelium (see Figure 15.7A)
iii. regeneration of ORNs, regrowth of ORN axons to the olfactory
bulb, specific targeting of ORN axons to the correct glomeruli,
and plasticity in central olfactory circuits may not be 100%
efficient, so olfactory perception may remain permanently
altered following recovery from head trauma

5
 Chemical Senses—Overview & Olfaction

STUDY QUESTION
Which of the following statements concerning the encoding of olfactory signals is most accurate?
A. Most olfactory receptor neurons express a large number of different olfactory receptor genes.
B. There is a “labeled-line code” connecting the olfactory epithelium to the olfactory bulb, with a
1-to-1 mapping of olfactory receptor neurons to glomeruli.
C. There is a “combinatorial code” operating in the olfactory cortex, since individual cortical
neurons respond selectively to just one odorant.
D. Central olfactory structures operate using a “temporal code”, since nearly synchronous
oscillations in neural activity are broadly distributed when particular odorants are presented.

6
 Chemical Senses—Gustation

Medical Neuroscience | Tutorial Notes

Chemical Senses—Gustation

MAP TO NEUROSCIENCE CORE CONCEPTS1

NCC1. The brain is the body's most complex organ.
NCC3. Genetically determined circuits are the foundation of the nervous system.

LEARNING OBJECTIVES
After study of the assigned learning materials, the student will:
1. Characterize the peripheral and central organization of the gustatory system.
2. Discuss sensory transduction in gustatory receptor cells.
3. Describe information coding in the gustatory system.

TUTORIAL OUTLINE

I. Organization of the gustatory system

A. anatomical overview (see Figure 15.172)
1. chemical constituents of foods interact with taste receptors cells located on
epithelial specializations, called papillae, which contain the taste buds (see
Figure 15.18)
2. taste buds are distributed on the tongue, soft palate, epiglottis, pharynx and
upper esophagus
3. taste receptor cells make synapses on the peripheral axons of cranial nerves VII,
IX and X
a. anterior tongue (soft palate)  facial nerve (CN VII)
b. posterior tongue  glossopharyngeal nerve (CN IX)
c. epiglottis (esophogus)  vagus nerve (CN X)
4. these central axons project into the solitary tract and synapse in the rostral
division of the nucleus of the solitary tract
a. the posterior division of this nucleus is a visceral sensory relay (more on
that in Unit 4 of this course)

1
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1
 Chemical Senses—Gustation

b. integration of gustatory and visceral sensory inputs across the rostral-

caudal axis of this nucleus facilitates appropriate visceral motor
activities in response to harmful tastants, such as gagging or vomiting
5. the nucleus of the solitary tract projects to a distinct part of the ventral
posterior complex in the thalamus
6. this part of the ventral posterior complex projects to several cortical areas,
including areas in the rostral insula and the frontal operculum (in the depth of
the rostral lateral fissure)
7. these cortical regions are interconnected with the posterior orbital prefrontal
cortex, where olfactory, gustatory and somatic sensory information is combined
to produce flavor sensations from which the hedonic values of foods are
represented
B. sensory transduction (see Figure 15.20)
1. taste receptor cells have a variety of transduction mechanisms (see Figure 15.21)
a. some tastants interact with receptors on ion channels in the apical tip of
the cell; the opening of Na+ channels or the closing K+ channels leads to
the generation of a receptor potential
b. other tastants interact with G-protein coupled receptors that use
second messengers to elevate intracellular Ca++ concentrations and
depolarize the membrane
2. depolarization and elevated intracellular Ca++ leads to the exocytosis of a
chemical neurotransmitter (serotonin), which binds to receptors on the sensory
axon
C. gustatory coding & perception
1. tastant identity is encoded by the activation of different receptors that are most
sensitive to distinct chemical substances (see Figure 15.19)
a. there are receptors that are especially sensitive to:
i. sucrose (sweet)
ii. NaCl (salt)
i. HCl (acid)
ii. quinine (bitter)
iii. glutamate (Japanese, “umami” = “delicious”)
b. detection thresholds are higher for substances that are important in our
diet (e.g., salts and carbohydrates); in the millimolar range
c. detection thresholds are lower for potential harmful compounds (bitter-
tasting alkaloids); in the nanomolar range
2. the concentration of a tastant is generally correlated with the number of
receptor cells activated and the intensity of afferent activation, as well as the
perceived intensity of the taste

2
 Chemical Senses—Gustation

3. in central gustatory centers, as in olfactory centers, there are no obvious ‘maps’

or systematic representations of tastants or the sensory periphery
4. the nature of the gustatory code remains obscure, but it appears to operate
according to a “labeled-line” code
i. different tastants activate distinct classes of receptor neurons that
make synaptic contact onto peripheral processes of afferent neurons
that are “labeled” by receptor specificity
ii. the responses of subcortical central neurons are tuned for tastant
identity, reflecting receptor specificity
iii. nonetheless, at higher centers of processing (especially in the orbital
cortex), the hedonic value of food becomes the most salient feature of
representation, rather than the molecular identity of any particular
tastant

STUDY QUESTION
Which of the following statements concerning the encoding of gustatory signals is most accurate?
A. Most gustatory receptor neurons express the full complement of genes that encode the five
basic classes of gustatory receptors.
B. Subcortical gustatory processing appears to implement a “labeled-line code” with the neural
responses of sensory cells reflecting the molecular properties of the gustatory receptors that
drive the response.
C. There is a “combinatorial code” operating in the orbital cortex, since individual cortical neurons
respond selectively to just one tastant.
D. At higher stages of gustatory processing in the brain, the most salient property of food is the
relative concentration of sour, bitter, salty, sweet, and “glutamate-like” tastants.

3
 Chemical Senses— Trigeminal Chemosensation

Medical Neuroscience | Tutorial Notes

Chemical Senses—Trigeminal Chemosensation

MAP TO NEUROSCIENCE CORE CONCEPTS1

NCC1. The brain is the body's most complex organ.
NCC3. Genetically determined circuits are the foundation of the nervous system.

LEARNING OBJECTIVES
After study of the assigned learning materials, the student will:
1. Characterize the general organization of the trigeminal chemosensory system.
2. Discuss sensory transduction in polymodal C nociceptive neurons.

TUTORIAL OUTLINE

I. Trigeminal chemoreception
A. polymodal nociceptive (C) fibers in the ophthalmic (e.g., corneas), maxillary and
mandibular (e.g., mucous membranes in nose and mouth) branches of the trigeminal
nerve that are activated by chemical irritants (e.g., air pollutants, ammonia, capsaicin)
(see Figure Box 10A2)
1. irritants activate transient receptor potential (TRP) channels, most of which are
cation-selective ion channels
2. irritants can also activate olfactory and gustatory receptors at low concentration
(non-irritating concentrations)
3. at higher concentrations, they activate the polymodal nociceptive fibers of the
trigeminal system, presumably via the activation of TRP channels (which are
distinct from the channels that operate in olfaction and gustation)
B. the central processes of these fibers synapse in the spinal trigeminal nucleus and project
along with this division of the trigeminal pain & temperature system (see Figure 10.6B)
C. activation of these fibers can lead to a variety of protective physiological responses,
including increased salivation, sweating, tearing, increased nasal secretions,
vasodilation, bronchoconstriction
1. these reactions are protective as they dilute irritant chemicals and help prevent
inhalation or ingestion

1
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1
 Chemical Senses— Trigeminal Chemosensation

STUDY QUESTION
If you choose to eat hot and spicy food (as I sometimes do), why does your mouth burn and your scalp
sweat (among other visceral sensory and motor reactions)?
A. Capsaicin and related compounds in spicy food activate transient receptor potential (TRP)
channels on taste cells in taste buds.
B. Capsaicin and related compounds in spicy food activate transient receptor potential (TRP)
channels on free nerve endings of polymodal C nociceptive fibers in oral mucosa.
C. Signals pertaining to the activation of TRP channels are integrated in the nucleus of the solitary
tract in the dorsal tegmentum of the caudal pons and upper medulla.
D. Signals pertaining to the activation of TRP channels are integrated in the spinal trigeminal
nucleus in the lateral tegmentum of the caudal pons and medulla.
E. Central processing of signals derived from TRP channel activation are distributed to integrative
centers in the hypothalamus and brainstem where visceral motor commands are distributed to
sweat-promoting preganglionic (sympathetic) neurons.
F. Central processing of signals derived from TRP channel activation are distributed to higher brain
centers where sensations are elaborated in cortical networks.
G. All of the above.

2
 Lower Motor Neuronal Control—Overview and Motor Units

Medical Neuroscience | Tutorial Notes

Lower Motor Neuronal Control—Overview and Motor Units

MAP TO NEUROSCIENCE CORE CONCEPTS1

NCC1. The brain is the body's most complex organ.
NCC3. Genetically determined circuits are the foundation of the nervous system.

LEARNING OBJECTIVES
After study of the assigned learning materials, the student will:
1. Discuss the general somatotopic organization of motor neurons in the ventral horn of the spinal
cord.
2. Characterize the motor unit and discuss different types of motor units.

TUTORIAL OUTLINE

I. Introduction
A. Overall organization of the neural centers that control movement (see Figure 16.12)
1. spinal cord circuits: “final common pathway” or “basic motor system”
a. segmental reflexes involving alpha (and gamma) motor neurons (i.e.,
“lower motor neurons”), local circuit interneurons, and afferent
somatic sensory input (e.g., myotatic or “knee-jerk” reflex)
b. intersegmental reflexes mediated by interneurons that coordinate the
activities of segmental circuits at multiple levels of the spinal cord (and
brainstem) (e.g., central pattern generators for locomotion)
2. descending control systems
a. volitional somatic movement: pyramidal motor system
(i) motor cortex (primary motor cortex and premotor cortex) plans
and directs the execution of volition movements (“pyramidal” --
outflow from the motor cortex is directed down the pyramidal
tract; i.e., via the medullary pyramids)
b. involuntary somatic movement (“extrapyramidal” -- outflow does not
involve the pyramidal tract)

1
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1
 Lower Motor Neuronal Control—Overview and Motor Units

(i) brainstem centers (reticular formation, vestibular nuclei,

superior colliculus) coordinate somatic motor activities that are
largely involuntary (e.g., postural adjustments and orienting
reflexes toward sensory stimuli)
(ii) limbic centers in the forebrain (amygdala, orbital-medial
prefrontal cortex, hypothalamus) also motivate movement
(important in emotional or appetitive behavior, as well as
addictive behavior)
c. visceral motor activity -- related to homeostasis and emergency
responses (“fight or flight”), and the expression of emotional behavior
(i) activities are usually integrated with somatic motor behavior
3. major brain systems that modulate descending control systems
a. basal ganglia (dorsal stream) selects and initiates appropriate motor
programs and suppresses inappropriate motor programs
b. cerebellum adjusts motor programs “on-line” with the aid of
proprioceptive feedback

II. Spinal Cord Circuitry and the Control of Movement

A. distribution of lower motor neurons
1. spinal cord (see Appendix Figure A4-A6, Table A1, and Figure 16.2)
a. motor neurons (both alpha and gamma) are located in the ventral horn
of the spinal cord
b. the motor neuronal pool for a given muscle (i.e., all the motor neurons
that innervate a muscle) forms a rod-shaped column that spans several
cord segments
c. somatotopy within the ventral horn
(i) segmental organization: cervical and lumbar enlargements
contain motor neurons that govern the arms and legs
(ii) organization across the ventral horn (see Figure 16.3)
- neurons that innervate axial and proximal musculature
are located medially in the ventral horn
- neurons that innervate the distal extremity are located
laterally in the ventral horn
2. brainstem (see Appendix Figure A8)
a. motor neurons are located in cranial nerve nuclei in the dorsal-medial
(somatic motor) and paramedian (branchial motor) zones
b. the motor neuronal pool for a given muscle forms a column or cluster in
a brainstem motor nucleus
B. The motor unit and its recruitment

2
 Lower Motor Neuronal Control—Overview and Motor Units

1. motor unit = an alpha motor neuron and the muscle fibers it innervates (see
Figures 16.5 & 16.6)
a. slow motor units
b. fast fatigue-resistant motor units
c. fast fatigable motor units
2. regulation of muscle force
a. size principle: slow motor units are recruited first, then fast fatigue-
resistant motor units, and finally fast fatigable motor units (Figure 16.7)
b. provides for the matching of the physiological properties of different
motor unit types with the demands of specific motor task
c. motor units are subject to use-dependent plasticity (see Box 16A)

STUDY QUESTION
Q1. What kinds of neurons innervate skeletal muscle?
A. neurons in the motor cortex
B. neurons in the cerebellum
C. neurons in the basal ganglia
D. neurons in the ventral horn of the spinal cord
E. neurons in the dorsal horn of the spinal cord

Q2. Make fist. Now squeeze harder. What just happened?

A. When you squeezed harder, you recruited additional smaller motor units than the ones
that were first activated.
B. When you squeezed harder, you recruited additional larger motor units than the ones
that were first activated.
C. When you squeezed harder, you decreased the activity of lower motor neurons in the
ventral horn of the cervical spinal cord.

3
 Lower Motor Neuronal Control—Segmental Reflexes

Medical Neuroscience | Tutorial Notes

Lower Motor Neuronal Control—Segmental Reflexes

MAP TO NEUROSCIENCE CORE CONCEPTS1

NCC1. The brain is the body's most complex organ.
NCC3. Genetically determined circuits are the foundation of the nervous system.

LEARNING OBJECTIVES
After study of the assigned learning materials, the student will:
1. Discuss the critical components of the myotatic reflex and how they interact to monitor and
adjust muscle length.
2. Characterize the role of gamma motor neurons in spindle gain adjustment.
3. Discuss the factors that account for muscle tone.
4. Discuss the critical components of the golgi tendon reflex and how they interact to monitor and
adjust the force of muscle contraction.
5. Discuss the critical components of the flexion/crossed-extension reflex and how they interact to
withdraw a limb from a harmful stimulus.

TUTORIAL OUTLINE

I. lower motor circuits

A. Overall organization of the neural centers that control movement (see Figure 16.12)
1. spinal cord circuits: “final common pathway” or “basic motor system”
a. segmental reflexes involving alpha (and gamma) motor neurons (i.e.,
“lower motor neurons”), local circuit interneurons, and afferent
somatic sensory input (e.g., myotatic or “knee-jerk” reflex)
b. intersegmental reflexes mediated by interneurons that coordinate the
activities of segmental circuits at multiple levels of the spinal cord (and
brainstem) (e.g., central pattern generators for locomotion)
B. segmental sensorimotor reflexes
1. myotatic (muscle spindle) reflex: a system that monitors and maintains muscle
length (see Figure 16.10)
a. stimulus: stretch of muscle

1
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1
 Lower Motor Neuronal Control—Segmental Reflexes

b. sensor: muscle spindle; specifically, sensory endings (group Ia and II

fibers) coiled around the intrafusal fibers of the muscle spindle
c. muscle spindles (see Figure 16.10A)
(i) within skeletal muscle are encapsulated, muscle spindles, which
contain a small number of intrafusal muscle fibers in parallel
with the extrafusal, striated muscle fibers
(ii) two types of intrafusal fibers: nuclear bag fibers and nuclear
chain fibers, so-named because of the arrangement of nuclei
within each type of fiber
(iii) primary sensory endings from group Ia afferent fibers encircle
both types of intrafusal fibers; group II afferent fibers innervate
nuclear chain fibers
(iv) stretch can activate the spindle fibers in one of two ways:
- passive stretch of the entire muscle (both intrafusal and
extrafusal fibers are stretched)
- contraction of the intrafusal muscle fibers themselves
by stimulation of the gamma motor neurons that
innervate the contractile segments of intrafusal fibers
(v) nuclear bag fibers respond phasically to dynamic changes in
muscle length
(vi) nuclear chain fibers respond tonically and proportionally to
muscle length
(vii) muscle spindles provide feedback signals to the cerebellum that
helps to regulate the strength of contraction (via dorsal
spinocerebellar and cuneocerebellar tracts)
(viii) muscle spindles also provide feedforward signals to the cerebral
cortex that contributes to conscious proprioception, (via the
dorsal column-medial lemniscal pathway) (see Lab Guide,
Appendix 1, Figure A1.6)
(ix) group Ia afferents also provide direct feedback to alpha motor
neurons in the ventral horn
d. central effects of afferent activity (see Figures 1.7 & 16.10; see also
Chapter 16 Animation 16.1 click here)
(i) monosynaptic excitation of motor neurons that innervate the
extrafusal fibers of the homonymous (same) muscle
(ii) monosynaptic excitation of motor neurons that innervate the
extrafusal fibers of synergistic muscles
(iii) disynaptic inhibition of the alpha motor neurons that innervate
the extrafusal fibers of antagonistic muscles (reciprocal
innervation)

2
 Lower Motor Neuronal Control—Segmental Reflexes

e. gain control
(i) gain: the amount of extrafusal contraction elicited by a given
stretch (load) applied to the muscle (output/input)
- if gain is low, a moderate stretch will induce a low rate
of firing in spindle afferent fibers and result in a low
degree of extrafusal contraction
- if gain is high, the same degree of stretch will induce a
higher rate of firing in spindle afferent fibers and result
in a higher degree of extrafusal contraction
(ii) gain adjustments may be made by alterations in the firing of
gamma motor neurons (see Figure 16.11)
- gamma motor neurons innervate the contractile
segments of intrafusal muscle fibers
- activation of gamma motor neurons leads to
contraction and shortening of intrafusal fibers
- changes in the length of intrafusal fibers “re-sets” the
sensitivity of the muscle spindle to stretch of the whole
muscle
(iii) gain adjustments are necessary when the muscle is shortening
to prevent the muscle spindle from being “unloaded”
(iv) gain adjustments may be context dependent
- gamma motor neuron activity may be adjusted
independently of alpha motor neurons by descending
projections from higher motor centers
- in anticipation of a difficult motor task or in preparation
for “fight or flight”, gamma motor neuron activity
increases, as does spindle sensitivity
- reflex gain is also dependent upon the excitability of
alpha motor neurons, which can also be modulated by
descending inputs from the brainstem reticular
formation (biogenic amine neurotransmitters)
- the synaptic terminals of Ia afferent fibers are subject to
axo-axonal (presynaptic) inhibition by local inhibitory
(GABAergic) neurons in the ventral horn
f. muscle tone (see Chapter 17, Box 17E)
1. resting level of tension in a muscle
2. depends upon the resting firing rate of alpha motor neurons
(i) in turn, this is dependent mainly upon the activity of
muscle spindle afferents

3
 Lower Motor Neuronal Control—Segmental Reflexes

(ii) gamma motor neuron activity establishes the gain of

the muscle spindle, which then influences the overall
level of muscle tone
Consider whether you think psychological stress might cause an
increase in firing of cervical gamma motor neurons. Might PT (e.g.,
massage) provide tools for resetting the gain of spindle activity?
3. damage to the dorsal roots (spindle afferents), ventral roots
(alpha and gamma motor neurons) or the spinal cord itself
generally results in loss of muscle tone, termed hypotonia
(lower motor neuron sign)
4. damage to descending pathways that modulate spinal reflexes
generally produce an increase in muscle tone, termed
hypertonia (upper motor neuron sign)
2. Golgi tendon organ reflex: a system that monitors and maintains muscle force
(see Figure 16.12 & 16.13)
a. stimulus: tension due to muscle contraction (insensitive to stretch)
b. sensor: golgi tendon organ, which consists of nerve endings of group Ib
afferents woven into the “fabric” of the collagen fibrils near the junction
of the muscle and tendon (in series with muscle fibers)
c. central effects of afferent activity
(i) disynaptic inhibition of the alpha motor neurons that innervate
the extrafusal fibers of the homonymous muscle
(ii) disynaptic excitation of alpha motor neurons that innervate the
extrafusal fibers of antagonistic muscles
(iii) because of some level of tonic activity in Ib afferents, Golgi
tendon organs help to maintain a steady level of muscle force
(e.g., counteracting the effects of fatigue)
(iv) as large forces are generated by muscle contraction, Golgi
tendon organ activity provides negative feedback signals that
protect against excessive (potentially damaging) tensions
d. subject to modulation by descending systems and input from other
sensory fibers (via group Ib interneurons)
(i) descending control from higher motor control centers provides
a means of allowing for maximal force generation, when the
risks are justified (e.g., “fight or flight” conditions, athletic
performance, resistance training)
e. compare function of muscle spindles and Golgi tendon organs with
passive stretch and active contraction of a muscle (see Figure 16.12)
3. flexion/crossed-extension reflex pathways: a system for withdrawing the limb
from a noxious stimulus (see Figure 16.14; see also Chapter 16 Animation 16.2
click here)
a. stimulus: activation of peripheral nociceptors

4
 Lower Motor Neuronal Control—Segmental Reflexes

b. sensor: sensory endings (group Aδ) in skin, joints, periosteum, etc.

c. central effects of afferent activity: ipsilateral flexion & contralateral
extension (for postural stability)
(i) disynaptic excitation of alpha motor neurons that innervate the
extrafusal fibers of flexor muscles in the same limb
(ii) disynaptic inhibition of alpha motor neurons that innervate the
extrafusal fibers of extensor muscles in the same limb
(iii) polysynaptic excitation of alpha motor neurons that innervate
the extrafusal fibers of extensor muscles in the opposite limb
(iv) polysynaptic inhibition of alpha motor neurons that innervate
the extrafusal fibers of flexor muscles in the opposite limb
d. also subject to descending modulation (e.g., fire-walkers)

STUDY QUESTION
Q1. Make a fist. Now squeeze harder. What just happened?
A. Activity in the Ia afferents associated with the contracting muscles were increased
substantially.
B. Activity in the Ia afferents associated with the contracting muscles were decreased
substantially.
C. Activity in the Ib afferents associated with the contracting muscles were increased
substantially.
D. Activity in the Ib afferents associated with the contracting muscles were decreased
substantially.
E. Activity in the alpha motor neurons associated with the contracting muscles were
decreased substantially.

Q2. What change in neural activity is associated most directly with an increase in the gain of
myotatic (muscle spindle) reflexes?
A. Increase in the firing of gamma motor neurons.
B. Increase in the firing of alpha motor neurons.
C. Decrease in the firing of Ia afferent neurons.
D. Decrease in the firing of Ib afferent neurons.

5
 Lower Motor Neuronal Control—Central Pattern Generators

Medical Neuroscience | Tutorial Notes

Lower Motor Neuronal Control—Central Pattern Generators

MAP TO NEUROSCIENCE CORE CONCEPTS1

NCC1. The brain is the body's most complex organ.
NCC3. Genetically determined circuits are the foundation of the nervous system.

LEARNING OBJECTIVES
After study of the assigned learning materials, the student will:
1. Describe central pattern generators and their significance for locomotion and other rhythmic
behavior.

TUTORIAL OUTLINE

I. Overall organization of the neural centers that control movement

A. spinal cord circuits: “final common pathway” or “basic motor system” (see Figure 16.12)
1. segmental reflexes involving alpha (and gamma) motor neurons (i.e., “lower
motor neurons”), local circuit interneurons, and afferent somatic sensory input
(e.g., myotatic or “knee-jerk” reflex)
2. intersegmental reflexes mediated by interneurons that coordinate the activities
of segmental circuits at multiple levels of the spinal cord (and brainstem) (e.g.,
central pattern generators for locomotion)
II. Central pattern generation
A. spinal cord circuits are capable of coordinating rhythmical activities of the extremities to
produce locomotory behaviors, such as walking, running, and even swimming or flying
(in some species)
B. comparable circuits are also present in the brainstem for the coordination of rhythmical
activities, such as respiration, chewing, swallowing and a variety of coordinated somatic
and visceral motor activities
C. general properties of central pattern generators:
1. some neurons in circuit function as “pacemakers”, by generating burst of spikes,
prolonged depolarizations or oscillatory activity
2. the expression of such pacemaker activity is usually initiated by descending
central command inputs or peripheral sensory inputs

1
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1
 Lower Motor Neuronal Control—Central Pattern Generators

3. the same circuit may produce different rhythms

D. in animal experiments, transection of the spinal cord of a cat above the lumbar
enlargement will not abolish coordinated walking movements of the hindlimbs if the cat
is placed on a moving treadmill (see Figure 16.15C)
1. not explained by simple reflexive response to passive stretch of muscle spindles
(behavior survives additional section of dorsal roots)
2. basic pattern of coordinated activity is “wired” into the segmental circuits of the
spinal cord; i.e., central pattern generator
E. normally, intersegmental connections coordinate the activities of central pattern
generators in cervical and lumbar enlargements to produce locomotory behavior
F. as in all other considerations of spinal cord circuitry, central pattern generators are
subject to descending control and modulation
G. difficulty in eliciting walking behavior in human spinal cord patients suggests that
descending controls play a larger role in coordinating or facilitating central pattern
generation in the human spinal cord

STUDY QUESTION
Which of the following behaviors do you think is mediated by central pattern generators?
A. walking
B. running
C. swimming
D. scratching
E. laughing
F. chewing
G. breathing
H. all of the above

2
 Lower Motor Neuronal Control—Lower Motor Neuron Syndrome

Medical Neuroscience | Tutorial Notes

Lower Motor Neuronal Control—Lower Motor Neuron Syndrome

MAP TO NEUROSCIENCE CORE CONCEPTS1

NCC1. The brain is the body's most complex organ.
NCC3. Genetically determined circuits are the foundation of the nervous system.

LEARNING OBJECTIVES
After study of the assigned learning materials, the student will:
1. Characterize the signs associated with damage to lower motor neurons.

TUTORIAL OUTLINE

I. Introduction
A. Overall organization of the neural centers that control movement (see Figure 16.12)
1. spinal cord circuits: “final common pathway” or “basic motor system”
a. segmental reflexes involving alpha (and gamma) motor neurons (i.e.,
“lower motor neurons”), local circuit interneurons, and afferent
somatic sensory input (e.g., myotatic or “knee-jerk” reflex)
b. intersegmental reflexes mediated by interneurons that coordinate the
activities of segmental circuits at multiple levels of the spinal cord (and
brainstem) (e.g., central pattern generators for locomotion)
2. descending control systems
a. volitional somatic movement: pyramidal motor system
(i) motor cortex (primary motor cortex and premotor cortex) plans
and directs the execution of volition movements (“pyramidal” --
outflow from the motor cortex is directed down the pyramidal
tract; i.e., via the medullary pyramids)
b. involuntary somatic movement (“extrapyramidal” -- outflow does not
involve the pyramidal tract)
(i) brainstem centers (reticular formation, vestibular nuclei,
superior colliculus) coordinate somatic motor activities that are
largely involuntary (e.g., postural adjustments and orienting
reflexes toward sensory stimuli)

1
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 Lower Motor Neuronal Control—Lower Motor Neuron Syndrome

(ii) limbic centers in the forebrain (amygdala, orbital-medial

prefrontal cortex, hypothalamus) also motivate movement
(important in emotional or appetitive behavior, as well as
addictive behavior)

II. Lower motor neuron syndrome

B. presentation of clinical signs and symptoms is distinct for damage to lower and upper
motor neurons (to be discussed in a later tutorial)
C. damage to lower motor neurons interrupts the ability of the CNS to control the
contractions of skeletal muscle
D. the clinical picture usually entails:
1. neural consequences
a. muscle paralysis (loss of volitional control) or paresis (partial paralysis or
profound weakness)
b. areflexia (loss of reflexes)
c. loss of muscle tone
2. muscle consequences
a. muscle atrophy
b. fibrillations (spontaneous twitches of denervated muscle fibers)and
fasciculations (abnormal excitability and activity of motor units)

STUDY QUESTION
Which of the following neurological signs and symptoms would make you think that a patient you are
examining probably DID NOT suffer a lower motor neuron injury?
A. weakness when asked to contract against resistance
B. anesthesia when affected skin was light brushed
C. analgesia when affected skin was firmly pricked with a pin
D. increased myotatic reflexes in the affected limb
E. noticeable atrophy of muscles in the affected limb

2
 Upper Motor Neuronal Control

Medical Neuroscience | Tutorial Notes

Upper Motor Neuronal Control—Overview & Primary Motor Cortex

MAP TO NEUROSCIENCE CORE CONCEPTS1

NCC1. The brain is the body's most complex organ.
NCC3. Genetically determined circuits are the foundation of the nervous system.
NCC4. Life experiences change the nervous system.

LEARNING OBJECTIVES
After study of the assigned learning materials, the student will:
1. Discuss the neural centers that give rise to lateral and medial descending projections to lower
motor neurons.
2. Discuss the organization of the motor cortex and its contributions to the control of volitional
movement.
3. Characterize the representation of the body in the motor cortex and compare it to the
representation of the body in the primary somatic sensory cortex.
4. Discuss population coding in the motor cortex.

TUTORIAL OUTLINE
I. Introduction
A. General features of upper motor neuronal control
1. mosaic of motor control areas in the posterior frontal lobe that organize and
initiate the activities of lower motor circuits in the brainstem and spinal cord
2. governs the expression of specific motor behaviors that we choose to perform
(e.g., writing, sports, musical performance, speaking)
3. some areas govern specific motor behaviors over which we have less control
(e.g., emotional nuances in speech, “fight or flight” responses)
4. there are additional brainstem circuits that operate “behind the scenes” to
implement adjustments of posture and gain
5. there are lateral (skilled movements) and medial (supporting movements)
parallel pathways to lower motor neuronal pools

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1
 Upper Motor Neuronal Control

B. for voluntary movement, there is a volitional or somatic motor system (this is

sometimes called the “pyramidal motor system”, named for the pyramidal tract, the
major subcortical outflow of the motor cortex) (see Figure 17.12)
1. lateral component: governs the independent (“fractionated”) movements of
the lower face and distal extremities, conveyed via the corticobulbar and
corticospinal tracts
See tutorial on “Upper Motor Neuronal Control of Facial Expressions”
2. medial component: governs postural control and orienting movements of head
and neck conveyed via projections from brainstem nuclei (note: although these
functions are, strictly speaking, non-volitional, we include them here to
emphasize their service of other, more specific volitional movements)
3. this lateral/medial division of labor is a reflection of the organization of motor
neurons in the ventral horn of the spinal cord
C. for the expression of movements that are less volitional, often in the context of
emotional experience, there are additional pathways from the cortex and brainstem
that mediate emotional motor behavior; these neural centers and pathways comprise
an “emotional motor system” (see Figure 29.2)
1. lateral component: governs the expression of specific somatic and visceral
motor behaviors via diffuse projections that are not part of the pyramidal tract
2. medial component: modulates the gain of brainstem and
segmental/intersegmental spinal reflexes

II. Motor Control Centers in the Cerebral Cortex: lateral projections for volitional motor control
A. “Motor cortex” refers to the mosaic of cortical areas in the posterior frontal lobe that
are mainly concerned with the planning and execution of volitional movements; these
include the primary motor cortex and the premotor cortex (see Figure 17.2)
B. each of these divisions of the motor cortex gives rise to descending projections to lower
motor neuronal circuits in the brainstem and spinal cord
C. collectively, the motor cortex receives input from the motor nuclei of the thalamus
(ventral anterior/ventral lateral complex) and somatic sensory and visual input from
somatic sensory and visual cortical areas (“where” pathway) in the parietal lobe
D. primary motor cortex (Brodmann’s Area 4)
1. located in the anterior bank of the precentral gyrus
a. the origin of a large fraction of the corticospinal (pyramidal) tract
b. most descending projections (which arise from layer 5) terminate on the
dendrites of interneurons in local-circuit neuronal pools of the
brainstem and spinal cord
c. some output neurons (including the exceptionally large Betz cells) make
monosynaptic excitatory connection onto α motor neurons

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 Upper Motor Neuronal Control

2. this area is “primary” because it has the lowest threshold for the elicitation of
movements with electrical stimulation of any area in the cerebral cortex
3. the primary motor cortex governs the execution of volitional movements,
particularly those that involve the distal extremities in central personal space
4. somatotopy in the primary motor cortex
a. along the length of the central sulcus, there is a crude topographic
representation of the body’s musculature (see Figure 17.5)
(i) although similar to the somatotopic map in the primary somatic
sensory cortex, the topographic map in the primary motor
cortex is less columnar and, therefore, much less precise
(ii) e.g., rather than a systematic mapping of each digit in sequence
(such as exists in S1), there is a general hand region that cannot
be subdivided into representations of individual digits
(iii) neurons that are connected to lower motor neurons that
govern the movements of different digits are interspersed and
highly interconnected within this hand region
(iv) this arrangement allows for the dynamic assembly of functional
ensembles of neurons that orchestrate the coordinated
movements of the digits
(v) dynamic assembly of functional networks is subject to
experience-dependent modification
b. what is represented in the primary motor cortex? (an ongoing debate;
see Box 17B)
(i) movements! (not muscles) … and maybe even the intentions
(goals) of movements
(ii) encodes movements that engage the hand, lower face (mouth),
and the coordinated activity of hand and mouth
(iii) skilled manual behaviors in central personal space
- individuals with selective lesions of the primary motor
cortex can reach to grab small objects, but have
difficulties picking them up with their fingers
- some residual digit function may reflect preservation of
synergistic projections from other parts of the motor
cortex (and maybe the red nucleus)
c. how is movement coding implemented?
(i) “tuning properties” of any corticospinal neuron are broad, even
though movements may be highly specialized and specific
(ii) movements are encoded by the concurrent discharges of large
populations of neurons in the motor cortex; this is an example
of a “population code” in neural processing (see Figure 17.8)

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 Upper Motor Neuronal Control

STUDY QUESTION
What features best differentiates the body map in the precentral gyrus (primary motor cortex) from the
post central gyrus (primary somatic sensory cortex)?
A. The central segment of the precentral gyrus represents the contralateral foot, while the central
segment of the postcentral gyrus represents the contralateral face.
B. The inferior segment of the precentral gyrus represents the contralateral face, while the central
segment of the postcentral gyrus represents the contralateral hand.
C. The medial portion of the precentral gyrus (in the paracentral lobule) represents the
contralateral hand, while the medial portion of the postcentral gyrus represents the
contralateral face.
D. The body map in the precentral gyrus faithfully represents the detailed structure of the
contralateral body, especially with respect to the digits of the hand, while the body map in the
postcentral gyrus lacks such detail.
E. The body map in the precentral gyrus is actually not a map of the body and its parts per se, as it
is in the postcentral gyrus, but a map of movement intention.

4
 Upper Motor Neuronal Control—Premotor Cortex

Medical Neuroscience | Tutorial Notes

Upper Motor Neuronal Control—Premotor Cortex

MAP TO NEUROSCIENCE CORE CONCEPTS1

NCC1. The brain is the body's most complex organ.
NCC3. Genetically determined circuits are the foundation of the nervous system.
NCC4. Life experiences change the nervous system.

LEARNING OBJECTIVES
After study of the assigned learning materials, the student will:
1. Discuss the neural centers that give rise to lateral and medial descending projections to lower
motor neurons.
2. Discuss the organization of the motor cortex and its contributions to the control of volitional
movement.

TUTORIAL OUTLINE
I. Motor Control Centers in the Cerebral Cortex: lateral projections for volitional motor control
“Motor cortex” refers to the mosaic of cortical areas in the posterior frontal lobe that are mainly
concerned with the planning and execution of volitional movements; these include the primary motor
cortex and the premotor cortex (see Figure 17.22)
A. each of these divisions of the motor cortex gives rise to descending projections to lower
motor neuronal circuits in the brainstem and spinal cord
B. collectively, the motor cortex receives input from the motor nuclei of the thalamus
(ventral anterior/ventral lateral complex) and somatic sensory and visual input from
somatic sensory and visual cortical areas (“where” pathway) in the parietal lobe
C. premotor cortex
1. changing premotor concepts
a. traditionally thought to function at a “higher plane” in a functional
hierarchy of motor control by providing input to the primary motor
cortex that, in turn, commands volitional movements … this view is no
longer accepted!
b. comprises a mosaic of cortical areas that organize movement sequences
required to interact with objects and persons (e.g., reaching, grasping,

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 Upper Motor Neuronal Control—Premotor Cortex

writing, gesturing, talking), as well as to express movements that convey

meaning (e.g., music performance, dance, emotive posturing)
c. mainly concerned with planning and expressing skilled movements in
“extrapersonal” space (see Box 17B)
2. includes areas just anterior to the precentral gyrus on the dorsal-lateral
convexity and the paracentral lobule in the medial aspect of the hemisphere,
and a set of areas in the depths of cingulate suclus (see Figures 17.2 and 17.9)
3. contributes axons to descending corticospinal (pyramidal) tract, but also
projects to brainstem reticular formation
4. for simplicity, consider medial and lateral divisions of premotor cortex:
a. medial premotor areas
(i) includes “cingulate motor areas” that contribute to the
expression of emotional behavior (see below)
(ii) some areas play a role in organizing complex movements,
especially movements that require bilateral hand coordination
(iii) other areas are involved in the organization of self-initiated
movements that are not triggered by sensory cues (e.g., front
eye fields, which shift gaze toward a desired visual target; see
Figures 20.11 & 20.12)
b. lateral premotor areas
(i) includes areas that play a role in organizing movements that are
guided by sensory information (conditioned motor responses)
(iii) another (Broca’s area in the left inferior frontal gyrus) is
specialized for the production of speech
(iv) others are involved in imitation learning (see Figure 17.10)
- inferior-anterior areas contain mirror neurons that fire
when the hand reaches and grasps an object and when
the same action is performed by another is observed
- such neurons may encode the intentions of others

STUDY QUESTION
Consider what you would do should you be driving a motor vehicle and you approach a typical,
international 3-color traffic light, and the light changes from green to yellow. I trust that the well-
practiced motor response in this circumstance is a gentle application of the brake (not the accelerator!)
so that you come to a stop in advance of the anticipated change in color from yellow to red. With this
scenario in mind, here’s the question: which division of the premotor cortex was chiefly engaged with
planning to execute the appropriate motor response given the color change in the traffic light?
A. the medial division of the premotor cortex
B. the lateral division of the premotor cortex

2
 Upper Motor Neuronal Control—Brainstem

Medical Neuroscience | Tutorial Notes

Upper Motor Neuronal Control—Brainstem

MAP TO NEUROSCIENCE CORE CONCEPTS1

NCC1. The brain is the body's most complex organ.
NCC3. Genetically determined circuits are the foundation of the nervous system.
NCC4. Life experiences change the nervous system.

LEARNING OBJECTIVES
After study of the assigned learning materials, the student will:
1. Discuss the neural centers that give rise to medial descending projections from the brainstem to
lower motor neurons.

TUTORIAL OUTLINE
I. Motor Control Centers in the Brainstem: medial components for somatic motor control
A. vestibular nuclei
1. descending projections from the vestibular nuclei reach the medial ventral horn
via medial and lateral vestibulospinal pathways (see Figures 14.11 2 & 17.2A)
a. medial: to the upper cervical cord that regulates head and neck position
b. lateral: to motor neurons in the medial ventral horn that excite extensor
muscles in the trunk and limbs
i. this pathway mediates balance adjustments and maintenance
of an upright posture
ii. although this is called the “lateral vestibulospinal” projection, its
termination is still within the medial motor neuron pools that
innervate more proximal musculature
2. these projections provide sensory feedback from the vestibular system that
adjusts posture given changes in the movements of the head
B. reticular formation
1. a complicated network of neurons (reticular means “net”) located in the core
(i.e., tegmentum) of the brainstem (see Figure 17.12 and Box 17D)

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 Upper Motor Neuronal Control—Brainstem

a. few discrete nuclei are easily recognized anatomically

b. clusters of neurons are scattered among long bundles of axons
2. descending projections from various pools of neurons synapse on interneurons
in the medial ventral horn (see Figure 17.11B)
a. gives rise to feedforward adjustments of posture that anticipate
changes in body biomechanics (see Figures 17.1`3 & 17.14)
b. reticular neurons receive input from “higher” motor centers in the
cortex that account for anticipatory adjustments (see Figure 17.15)
3. among the other important functions of the reticular formation are:
a. regulation of sleep and wakefulness
b. regulation of general levels of arousal (and possibly attention)
c. coordination of lower motor neuronal pools in the brainstem and spinal
cord (e.g., “gaze” centers for eye movements; see Figure 20.8)
d. control of critical cardiovascular and pulmonary functions
e. control of diverse visceral motor activities (e.g., micturition, defecation,
vomiting, glandular secretions)
C. superior colliculus (see Figure 20.9)
1. integrates sensory information and produces reflexive gaze shifts toward
sensory stimuli that usually require postural adjustments
2. projects (mainly indirectly) to the medial ventral horn of the cervical
enlargement (via connections through the reticular formation) to coordinate
orienting response of head and neck

STUDY QUESTION
Imagine that you are a runner at the starting line of a race and you are anticipating the sound of the
starter’s signal. You are in the “ready … set” posture awaiting the “go” signal. Your body is ready for
action at the sound of that signal. Which descending tract provides the appropriate signals that prepare
the body for action in advance of the “go” signal?
A. medial vestibulospinal tract
B. lateral vestibulospinal tract
C. lateral corticospinal tract
D. reticulospinal tract
E. tectospinal tract

2
 Emotional Motor System

Medical Neuroscience | Tutorial Notes

Upper Motor Neuronal Control—Emotional Motor System

MAP TO NEUROSCIENCE CORE CONCEPTS1

NCC1. The brain is the body's most complex organ.
NCC3. Genetically determined circuits are the foundation of the nervous system.
NCC4. Life experiences change the nervous system.

LEARNING OBJECTIVES
After study of the assigned learning materials, the student will:
1. Discuss the evidence for an “emotional motor system”.

TUTORIAL OUTLINE
I. Emotional Motor System (see Figure 29.22)
A. originates mainly within neural centers of the ‘limbic’ forebrain that coordinate
emotional integration; these include the cingulate gyrus, orbital and medial prefrontal
cortex, the amygdala and the hypothalamus
B. this (largely) non-volitional motor system is for:
1. the expression and experience of emotional, motivated or appetitive behavior
2. preparations for and the execution of emergency (“fight or flight”) behaviors
C. these forebrain structures give rise to medial and lateral descending projections
1. medial component (e.g., during stressful or threatening circumstances,
preparation for maximal motor activity with neglect of painful stimuli)
a. terminates in the medial reticular formation, which in turn gives rise to
projections that modulate lower motor circuits (and sensory neurons)
b. mediates widespread influence on the excitability of lower motor
neurons and the local interneurons that organize their output
2. lateral component (e.g., regulation of cardiovascular and respiratory function,
salivation, vocalization (non-speech), facial expression, micturition, vomiting)
a. terminates in the lateral reticular formation and cranial nerve nuclei
that govern somatic and visceral motor aspects of emotional expression

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 Emotional Motor System

D. examples of integrated activity of the emotional motor system

1. facial expressions (see Chapter 29, Box 17A and Box 29A): illustrates parallel
pathways that govern certain muscles
2. speech: illustrates the coordinated contributions of volitional motor and
emotional motor systems in the expression of an integrated behavior

STUDY QUESTION
You are trying your best to smile for a camera, but you are not all that happy about having your picture
taken. Which part of the motor cortex is likely governing that forced smile?
A. the paracentral lobule
B. the inferior segment of the precentral gyrus, just inferior to where the “S-shaped” bend
is typically found in the central sulcus
C. the central portion of the precentral gyrus where the “S-shaped” bend is typically found
in the central sulcus
D. the cingulate motor area, which is a division of the medial premotor cortex in the banks
of the cingulate sulcus

2
 Upper Motor Neuronal Control—Upper Motor Neuron Syndrome

Medical Neuroscience | Tutorial Notes

Upper Motor Neuronal Control—Upper Motor Neuron Syndrome

MAP TO NEUROSCIENCE CORE CONCEPTS1

NCC1. The brain is the body's most complex organ.
NCC3. Genetically determined circuits are the foundation of the nervous system.
NCC4. Life experiences change the nervous system.

LEARNING OBJECTIVES
After study of the assigned learning materials, the student will:
1. Discuss the signs associated with damage to upper motor neurons.

TUTORIAL OUTLINE
I. Upper motor neuron syndrome
A. presentation of clinical signs and symptoms of upper motor neuronal injury should be
distinguished from those associated with damaged lower motor neurons (Table 17.12)
B. initially, spinal shock occurs, which is characterized by flaccid paralysis (profound loss of
muscle tone); this may resemble the signs of lower motor neuronal injury
C. however, after several days to weeks, a consistent set of motor signs emerges:
1. the Babinski sign: abnormal extensor plantar response to firm stroke of the
sole of the foot (see Figure 17.16); but not a very sensitive sign
2. muscle spasticity: increased muscle tone, hyperactive segmental reflexes,
clonus (oscillatory motor response to muscle stretch) (see Box 17E)
a. decerebrate rigidity: greatly increased tone of extensor muscles in legs
and (typically) flexor muscles in arms and neck
b. “clasped-knife” response: resistance to passive stretch that suddenly
gives way (like closing the blade of a pocket knife)
3. paralysis or paresis, especially for fine movements of the distal extremities
D. persistent symptoms are explained by a loss of descending inputs from the cerebral
cortex that govern the expression of volitional movements and/or the loss of

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 Upper Motor Neuronal Control—Upper Motor Neuron Syndrome

descending inputs from the brainstem that modulate the gain of segmental and
intersegmental reflexes
E. suggests that the net effect of input from upper motor neurons to lower motor
neuronal circuits in the spinal cord is suppressive (because loss of input leads to
hyperreflexia and an increase in muscle tone)

STUDY QUESTION
Consider a patient who is now in the so-called “chronic” phase (after the first 3 months or so have
passed) following a stroke involving the right anterior cerebral artery. What signs and symptoms would
you expect to discover in this patient?
A. weakness in the left lower leg, with ankle clonus and a positive Babinski sign, all on the left
B. weakness in the right lower leg, with ankle clonus and a positive Babinski sign, all on the right
C. weakness in the left arm and hand, with spasticity and mild clonus at the wrist and elbow, all on
the left
D. weakness in the right arm and hand, with spasticity and mild clonus at the wrist and elbow, all
on the right
E. profound weakness in the left lower leg with flaccidity and evidence of muscle wasting in the
foot, all on the left
F. profound weakness in the right lower leg with flaccidity and evidence of muscle wasting in the
foot, all on the right

2
 Modulation of Movement by the Basal Ganglia

Medical Neuroscience | Tutorial Notes

Modulation of Movement by the Basal Ganglia

MAP TO NEUROSCIENCE CORE CONCEPTS1

NCC1. The brain is the body's most complex organ.
NCC3. Genetically determined circuits are the foundation of the nervous system.
NCC4. Life experiences change the nervous system.

LEARNING OBJECTIVES
After study of the assigned learning materials, the student will:
1. Identify the major components of the basal ganglia, including the parts of the dorsal motor
stream and ventral limbic stream.
2. Discuss the role of the basal ganglia in the initiation and suppression of behavior.
3. Describe the principle of “disinhibition” and explain how it applies to the circuitry and functions
of the basal ganglia.
4. Discuss the critical role of dopamine in facilitating the function of basal ganglia circuitry.

TUTORIAL OUTLINE

I. Introduction
A. basal ganglia
1. collection of nuclei located deep in the anterior telencephalon that are
intimately related to the functions of the cerebral cortex
a. receive widespread inputs from the cerebral cortex
b. after several steps of processing, basal ganglia output is directed to the
thalamus, which in turn projects back to the cerebral cortex
c. thus, the overall function of the basal ganglia is to modulate thalamo-
cortical activity
2. there are multiple parallel processing “streams” through the basal ganglia (see
Box 18D2); three important streams are:
a. dorsal motor stream (motor loop)
b. dorsal cognitive (“executive”) stream (prefrontal loop)

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 Modulation of Movement by the Basal Ganglia

c. ventral limbic (“emotional”) stream (limbic loop)

B. general sense of basal ganglia function:
1. processes executive commands for the initiation of appropriate behavior and
the suppression of inappropriate behavior
2. diseases associated with the basal ganglia
a. hypokinetic movement disorders (e.g., Parkinsonism)
b. hyperkinetic movement disorders (e.g., Huntington’s disease,
hemiballism)
c. possibly, certain affective and cognitive disorders (e.g., depression,
schizophrenia, Tourette’s syndrome)
II. The circuitry
A. basic components of basal ganglia system (see Figure 18.1)
Table 1. Major components of the basal ganglia.

Dorsal Motor Stream Ventral Limbic Stream

(volitional movement) (emotional behavior)
Prefrontal cortex, amygdala,
Cortical input Sensory and motor cortex
hippocampal formation
Nucleus accumbens
Caudate nucleus
Striatum Ventral striatum (several small
Putamen
subdivisions)
Globus pallidus, internal segment
Ventral pallidum
Pallidum Globus pallidus, external segment
Substantia nigra, pars reticulata
Substantia nigra, pars reticulata
Substantia nigra, pars compacta
Modulatory inputs (dopamine) Ventral tegmental area (dopamine)
Subthalamic nucleus (glutamate)
Thalamic target of Ventral anterior/ventral lateral
Mediodorsal nucleus
output nuclei

B. inputs to basal ganglia (striatum)

1. input “commands” are relayed from widespread parts of cerebral cortex
a. dorsal motor stream (see Figure 18.2)
(i) receives “uni-modal” information from frontal motor areas,
parietal somatic sensory and visual areas, and temporal
auditory and visual areas
(ii) receives “multi-modal” (associational) information from areas in
frontal, parietal and temporal lobes

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 Modulation of Movement by the Basal Ganglia

(iii) receives modulatory (dopamine) inputs from substantia nigra,

pars compacta
b. ventral limbic stream (see Box 18D & Figure 29.10)
(i) receives sensory information from prefrontal cortical areas that
process olfaction, gustation and visceral-sensory inputs
(ii) receives associational information from additional sectors of the
prefrontal cortex, amygdala and hippocampal formation
(iii) receives modulatory (dopamine) inputs from the ventral
tegmental area (medial to the substantia nigra, pars compacta)
C. circuitry within the basal ganglia and outputs to thalamo-cortical circuits
1. dorsal motor stream (see Figure 18.7)
a. ‘direct’ pathway (from basal ganglia to thalamus)
(i) cerebral cortex  caudate/putamen
(ii) caudate/putamen  internal segment of the globus pallidus
(and substantia nigra, pars reticulata)
(iii) internal segment of globus pallidus (and substantia nigra, pars
reticulata)  ventral anterior/ventral lateral complex of the
thalamus
(iv) ventral anterior/ventral lateral complex  motor cortical areas
in frontal lobe
b. ‘indirect’ pathway (from basal ganglia to thalamus)
(i) cerebral cortex  caudate/putamen
(ii) caudate/putamen  external segment of the globus pallidus
(iii) external segment of globus pallidus  subthalamic nucleus
(iv) subthalamic nucleus  internal segment of the globus pallidus
(v) internal segment of globus pallidus  ventral anterior/ventral
lateral complex of the thalamus
(vi) ventral anterior/ventral lateral complex  motor cortical areas
in frontal lobe
2. ventral limbic stream
a. orbital-medial prefrontal cerebral cortex, amygdala and hippocampal
formation  ventral striatum (caudal-medial parts of caudate nucleus,
nucleus accumbens, other ventral striatal divisions)
b. ventral striatum  ventral pallidum (and substantia nigra, pars
reticulata)
c. ventral pallidum (and substantia nigra, pars reticulata)  mediodorsal
nucleus of the thalamus

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 Modulation of Movement by the Basal Ganglia

d. mediodorsal nucleus  prefrontal cortex

3. consideration of circuit function
a. disinhibition (study Figure 18.5)
b. direct and indirect pathways of the dorsal motor stream
(i) transient activation of caudate/putamen projection neurons
transiently inhibits projection neurons of the internal and
external segments of the globus pallidus
(ii) direct pathway (see Figure 18.7A):
- transient inhibition of projection neurons of the globus
pallidus internal segment removes tonic inhibition of
ventral anterior/ventral lateral complex
- ventral anterior/ventral lateral complex neurons are
transiently “released” activate motor cortex
(iii) indirect pathway (see Figure 18.7B)
- transient inhibition of the external segment of the
globus pallidus disinhibits the subthalamic nucleus
- subthalamic nucleus is then “released” to transiently
activate the internal segment of the globus pallidus
- activation of internal segment of globus pallidus
increases tonic inhibition of the ventral anterior/ventral
lateral complex
- ventral anterior/ventral lateral complex neurons are
inhibited from activating the motor cortex
(iv) both direct and indirect pathways are modulated by dopamine
in the striatum
(v) notice that the direct and indirect pathways have opposing
effects on the thalamo-cortical projection
(vi) the output of the basal ganglia (via the internal segment of the
globus pallidus) depends upon the balance of activity in the
direct and indirect pathways
c. ventral limbic stream (analogous to direct pathway)
(i) transient activation of ventral striatum projection neurons
transiently inhibits projection neurons in the ventral pallidum
and substantia nigra, pars reticulata
(ii) transient inhibition of pallidal projection neurons removes tonic
inhibition of neurons in the mediodorsal nucleus
(iii) neurons of the mediodorsal nucleus are transiently “released”
to activate prefrontal cortex

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 Modulation of Movement by the Basal Ganglia

STUDY QUESTIONS
Q1. Which of the following structures is a component of the “striatum”?
A. putamen
B. globus pallidus
C. substantia nigra pars compacta
D. substantia nigra pars reticulata
E. subthalamic nucleus

Q2. Which of the following structures is a component of the “pallidum”?

A. putamen
B. caudate nucleus
C. nucleus accumbens
D. substantia nigra pars compacta
E. substantia nigra pars reticulata
F. subthalamic nucleus

5
 Modulation of Movement by the Basal Ganglia—Normal and Abnormal Movement

Medical Neuroscience | Tutorial Notes

Modulation of Movement by the Basal Ganglia—Normal and Abnormal
Movement

MAP TO NEUROSCIENCE CORE CONCEPTS1

NCC1. The brain is the body's most complex organ.
NCC3. Genetically determined circuits are the foundation of the nervous system.
NCC4. Life experiences change the nervous system.

LEARNING OBJECTIVES
After study of the assigned learning materials, the student will:
1. Discuss the critical role of dopamine in facilitating the function of basal ganglia circuitry.
2. Explain hypokinetic movement disorders in terms of the function of basal ganglia circuitry.
3. Explain hyperkinetic movement disorders in terms of the function of basal ganglia circuitry.

TUTORIAL OUTLINE

I. Basal ganglia function

A. normal functions
1. general properties
a. neurons in the striatum fire action potentials before and during the
onset of movement
b. suggests a role for basal ganglia in initiation of movement, not the
ongoing coordination of movements (role played by cerebellum)
2. for both the dorsal motor and ventral limbic streams, the balance of activation
in the direct and indirect pathways serves to initiate the selected behavioral
program and suppress non-synergistic programs
3. conceptually, this is another example of “center” (initiation of intended
behavior) “surround” (suppression of unintended behavior) antagonism
(consider Figure 18.82)
B. abnormal function in disease states
1. Parkinson’s disease

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 Modulation of Movement by the Basal Ganglia—Normal and Abnormal Movement

a. symptoms: akinesia (lack of voluntary movement) or bradykinesia

(extreme slowness of voluntary movement), reduced facial expressions,
postural rigidity, resting tremor (e.g., “pill-rolling” tremor) in
arms/hands, shuffling (“festinating”) gait, difficulty initiating and
terminating movements, cognitive changes (dementia)
b. onset: typically after the fifth decade of life
c. pathology: loss of (>80%) dopaminergic neurons in the substantia nigra,
pars compacta
(i) by “natural” (genetic/epigenetic) causes; etiology is unknown
(ii) by abuse of MPTP (synthetic heroin)
d. consequences for basal ganglia function (see Figure 18.10A)
(i) decreased output from caudate/putamen to internal segment
of the globus pallidus
(ii) excessive tonic inhibition of ventral anterior/ventral lateral
complex of the thalamus
(iii) decrease activation of motor cortex via ventral anterior/ventral
lateral complex
2. Huntington’s chorea (autosomal dominant; onset between 30-50 years)
a. symptoms: involuntary choreic (“dance-like”) movements: may be jerky,
hyperkinetic, and/or dystonic; severe dementia then ensues
b. onset: usually in the 4th or 5th decades of life, with an average life
expectancy of about 15 years thereafter
c. pathology
(i) widespread degeneration of cerebral cortex and striatum
(ii) especially affected are striatal neurons that project to the
external segment of the globus pallidus (indirect pathway)
d. consequences for basal ganglia function (see Figure 18.10B)
(i) decreased output from caudate/putamen to external segment
of the globus pallidus
(ii) increased tonic inhibition of subthalamic nucleus
(iii) decreased drive of internal segment of globus pallidus via
subthalamic nucleus
(iv) decreased tonic inhibition of ventral anterior/ventral lateral
complex of the thalamus
(v) increased activation of motor cortex and via ventral
anterior/ventral lateral complex

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 Modulation of Movement by the Basal Ganglia—Normal and Abnormal Movement

STUDY QUESTION
In idiopathic Parkinsonism, there is pathological difficulty initiating movement. Which of the following
statements provides the best explanation of this difficulty?
A. There is too much activity in the external segment of the globus pallidus and, therefore,
insufficient inhibition of the ventral anterior/ventral lateral complex of the thalamus.
B. There is too much activity in the internal segment of the globus pallidus and, therefore,
too much inhibition of the ventral anterior/ventral lateral complex of the thalamus.
C. There is insufficient activity in the subthalamic nucleus and, therefore, insufficient
output from the internal segment of the globus pallidus.
D. The subthalamic nucleus is overactive, which results in the excessive disinhibition of the
ventral anterior/ventral lateral complex of the thalamus.
E. The substantia nigra pars compacta is overactive, which results in the excessive
disinhibition of the ventral anterior/ventral lateral complex of the thalamus.

3
 Modulation of Movement by the Cerebellum

Medical Neuroscience | Tutorial Notes

Modulation of Movement by the Cerebellum

MAP TO NEUROSCIENCE CORE CONCEPTS1

NCC1. The brain is the body's most complex organ.
NCC3. Genetically determined circuits are the foundation of the nervous system.
NCC4. Life experiences change the nervous system.

LEARNING OBJECTIVES
After study of the assigned learning materials, the student will:
1. Identify and discuss the basic parts of the cerebellum.
2. Characterize in general terms the major functions performed by the cerebellum.
3. Sketch the major inputs and output of the cerebellum.
4. Describe the circuitry involved in the main excitatory loop and inhibitory side-loop through the
cerebellum.
5. Discuss the means by which circuitry in the cerebellum aid to increase the success of volitional
motor performance.
6. Describe the clinical signs and symptoms associated with cerebellar damage.

TUTORIAL OUTLINE
I. Introduction
A. although the cerebellum’s elegant neural circuitry has been known for nearly a century,
a general understanding of function has been slow in coming
1. it is a massive brain structure (~10% of entire brain) and it contains ~50% of all
the neurons in the entire CNS
2. nevertheless, symptoms of cerebellar damage (e.g., ataxia; see below) are
relatively minor
B. general sense of cerebellar function
1. “error correction” = integrates executive commands with sensory feedback
regarding the external and internal environment for the moment-to-moment
adjustment of behavior

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1
 Modulation of Movement by the Cerebellum

2. learns new behavioral programs (both motor and non-motor behaviors) when
errors are numerous
3. coordinates ongoing multi-jointed movements (motor agility)
4. assists the premotor cortex in planning movements when motor learning has
been stored and errors are few
5. coordinates ongoing sequential cognitive processes (cognitive agility)
II. The circuitry
A. Overview of the basic components of the cerebellum
1. overall organization (see Figure 19.1A-C2 and Table 19.1)
a. major parts
(i) cerebellar cortex
(ii) deep cerebellar nuclei
(iii) cerebellar peduncles
b. three functional divisions (see Figure 19.4 and 19.5)
(i) spinocerebellum: receives proprioceptive information from
muscle spindles, as well as visual and auditory information
(ii) cerebrocerebellum (also called the neocerebellum): mainly
related to processing in the cerebral cortex
(iii) vestibulocerebellum (also called the flocculonodular lobe):
receives and sends input to the vestibular nuclei; closely related
to vestibular function
c. two levels of processing
(i) cerebellar cortex
(ii) deep cerebellar nuclei (the dentate nucleus, the interposed
nuclei, and the fastigial nucleus)
B. a closer look at cerebellar circuits
1. functional overview of inputs to the cerebellum
a. “executive” signals relayed from widespread parts of cerebral cortex in
the frontal and parietal lobes via the pontine nuclei: conveys the
commands for (motor) behavior
b. “feedback” signals from proprioceptive systems: conveys sensory
information about ongoing behavior
c. “learning” signals derived from the inferior olivary nucleus of the
medulla: facilitates adaptation (error correction)
2. anatomical overview of inputs to the cerebellum (see Figure 19.3)

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 Modulation of Movement by the Cerebellum

a. two types of afferent projections (see Figure 19.9 and 19.10)

(i) mossy fibers
- quantitatively, the most important source of input
- all inputs from brainstem and spinal cord, except inputs
from the inferior olivary nucleus
(ii) climbing fibers
- distinct inputs from the inferior olivary nucleus
- modulate the output of the cerebellar cortex
b. both types of afferents terminate in the cerebellar cortex and the deep
cerebellar nuclei
3. inputs reflect tripartite organization of cerebellum
a. spinocerebellum
(i) proprioceptive information about ipsilateral body, mainly
signals related to muscle spindles (see Lab Guide, Appendix 1)
(ii) for lower extremities, relayed via second order neurons in
dorsal nucleus of Clark (thoracic cord)
(iii) for upper extremities, relayed via second order neurons in the
external cuneate nucleus
(iv) also receives visual and auditory signals from brainstem
processing centers
(v) axons of second order neurons reach cerebellum as mossy
fibers through the ipsilateral inferior cerebellar peduncle
b. cerebrocerebellum
(i) receives highly processed sensory information (somatic
sensory, visual, auditory) and executive commands from
widespread regions of the contralateral cerebral cortex
(ii) relayed via corticobulbar fibers that terminate in the ipsilateral
pontine nuclei in the base of the pons
(iii) axons of pontine neurons decussate and project to the
cerebellar cortex as mossy fibers through the middle cerebellar
peduncle
c. vestibulocerebellum
(i) information about the position and movements of the head
(ii) inputs come mainly from vestibular nuclei in the brainstem
(iii) axons of second order neurons reach cerebellum as mossy
fibers through the ipsilateral inferior cerebellar peduncle

3
 Modulation of Movement by the Cerebellum

4. this arrangement of inputs means that the cerebellar hemisphere is concerned

with the ipsilateral side of the body
5. cerebellar processing
a. organization of the cerebellar cortex
(i) principal neurons: Purkinje cells
- provides output from cerebellar cortex to deep
cerebellar nuclei (and vestibular nuclei)
- inhibitory; use GABA as neurotransmitter
- high level of tonic activity at rest that is modulated
during movements (see Figure 19.11)
(ii) interneurons
- granule cells
- receive mossy fiber input
- give rise to parallel fibers that synapse on
Purkinje cells (and other interneurons)
- excitatory (glutamatergic)
- other inhibitory interneurons are present (stellate cells,
basket cells, Golgi cells)
b. flow of information through cerebellum circuits: processing through a
main excitatory loop and an inhibitory side-loop
(i) mossy fiber inputs
- mossy fibers send a collateral to neurons in the deep
nuclei of the cerebellum (= main excitatory loop)
- also synapse in cortical glomeruli (encapsulated,
specialized synaptic complexes) containing dendrites of
granule cells and other interneurons
- provide the information about the executive command
and the feedback sensory cues that are fundamental to
cerebellar processing
(ii) climbing fiber inputs
- make powerful synaptic contacts on the proximal
dendrites of Purkinje cells (hence, “climbing”)
- climbing fibers also send a collateral to neurons in the
deep nuclei of the cerebellum
- provide the “contextual” information to the cerebellum
(especially the Purkinje cells) for learning
(iii) granule cells drive an elongated “beam” of Purkinje cells via
their lengthy parallel fibers

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 Modulation of Movement by the Cerebellum

(iv) Purkinje cells integrate parallel fiber and climbing fiber inputs
and send inhibitory projections to the deep cerebellar nuclei (=
inhibitory side-loop)
- lateral parts of cerebellar cortex (mainly
cerebrocerebellum) projects to the dentate nucleus
- paramedian parts of the cerebellar cortex (lateral spino-
cerebellum) project to the interposed nuclei
- medial cerebellar cortex (medial spino-cerebellum)
project to fastigial nucleus
- and flocculonodular lobe (vestibulocerebellum) projects
directly to vestibular nuclei
(v) thus, deep cerebellar nuclei are excited by mossy (and climbing)
fiber inputs and inhibited by Purkinje cell inputs
(vi) strength of Purkinje cell output to deep cerebellar nuclei is
subject to use-dependent modification (plasticity):
- pairing of climbing fiber activation and parallel fiber
activity leads to a depression of Purkinje cell responses
to parallel fibers
- this means that activation of this inhibitory side-loop
may be weakened and, therefore, the output for the
deep cerebellar nuclei may be strengthened
- this is the cellular basis of learning in the cerebellum
C. outputs of cerebellar (see Figures 19.6-8): arise from the deep cerebellar nuclei
1. ascending output is directed toward thalamocortical circuits (see Figure 19.6)
a. dentate nucleus (and interposed nuclei)
(i) sends its axons out of the cerebellum through the superior
cerebellar peduncle, which then decussate
(ii) most dentate axons project directly to the contralateral ventral
lateral complex of the thalamus
- influence thalamocortical circuits concerned with motor
control and cognition in the motor cortex and
prefrontal cortex, respectively
- adjusts the planning and mental rehearsal of complex
motor movements and other cognitive tasks involving
the sequencing of multiple steps
2. “descending” output is directed toward brainstem circuits (see Figure 19.7)
a. fastigial nuclei
(i) project to medial upper motor neuron systems in the brainstem
reticular formation

5
 Modulation of Movement by the Cerebellum

(ii) output adjusts the control of posture, balance, gaze (i.e., typical
“medial” functions)
b. each deep cerebellar nucleus also projects to the red nucleus, which in
turn provides feedback signals to the source of the learning signals, the
inferior olivary nucleus (see Figure 19.6; see also Figure 19.3)
3. vestibulocerebellum (an exceptional division of the cerebellum)
a. as noted above, Purkinje cells in the flocculonodular lobe project
directly to vestibular nuclei in the brainstem
b. vestibular nuclei, as you know, then project to lower motor circuits that
govern eye movements and posture (see Figure 19.7)
III. Cerebellar function
A. coordination of ongoing, multi-jointed movement (error correction)
1. control of stability
2. actively damp oscillations
B. learning of new movements
1. adaptation of hand-eye coordination (Friday PM’s session)
2. learning can be remarkably specific
a. type of movements
b. body parts involved
C. initiation and planning of movements
D. cognition
1. timing judgements
2. sequencing of multiple steps (e.g., pegboard puzzle)
3. acquisition of mental skills that require repeated practice (cognitive agility)

IV. Cerebellar lesions: deficits in coordinating movements

A. because of the arrangement of inputs and outputs of the cerebellum, clinical (motor)
signs of cerebellar lesions are always ipsilateral to the lesion
B. cerebellar ataxia: incoordination of ongoing movements
1. intentional tremor: tremor during movement
2. dysmetria: instability of a limb as it approaches a target (overshooting or
undershooting)
3. rapid, repetitive movements impaired
4. decomposition of movements
C. cognitive deficits are possible (impairments of cognitive agility)

6
 Modulation of Movement by the Cerebellum

STUDY QUESTIONS
Q1. Which of the following events are critical for motor learning in the cerebellum?
A. insertion of new AMPA receptors in the dendritic spines of Purkinje neurons
B. insertion of new GABA receptors in the dendritic spines of Purkinje neurons
C. removal of GABA receptors from the dendritic spines of Purkinje neurons
D. activation of climbing fibers
E. induction of long-term potentiation at the parallel fiber-Purkinje neuron synapse

Q2. Which of the following signs and symptoms is indicative of dysfunction in cerebellar modulation
of movement?
A. hyporeflexia
B. hypereflexia
C. rigidity
D. flaccidity
E. ataxia
F. atonia
G. spasticity

7
 Eye Movements

Medical Neuroscience | Tutorial Notes

Eye Movements

MAP TO NEUROSCIENCE CORE CONCEPTS1

NCC1. The brain is the body's most complex organ.
NCC3. Genetically determined circuits are the foundation of the nervous system.

LEARNING OBJECTIVES
After study of the assigned learning materials, the student will:
1. Discuss the five major types of eye movements and indicate the functional purpose of each.
2. Discuss the neural circuits responsible for making a saccadic eye movement.
3. Discuss the roles of the frontal eye fields and the superior colliculus in directed gaze toward an
object of interest in the visual field.

TUTORIAL OUTLINE

I. Eye Movements
A. overview
1. because good visual acuity is restricted to a very small part of the visual field
(about two degrees), eye movements are necessary to:
a. maintain foveal fixation on a moving target
b. maintain foveal fixation on a target during head movements
c. acquire and fixate a new visual target
2. eye movements are a relatively simple set of somatic motor behaviors; there
are only 6 pairs of muscles involved and five patterns of movement
B. extraocular muscles and patterns of innervation
1. for each eye, there are three pairs of striated muscles that move the eye along
the three axes of rotation (review orbital anatomy; see Figure 20.22)
2. innervation by three cranial nerves (see Figure 20.3)
a. abducens (CN VI): ipsilateral lateral rectus muscle
b. trochlear (CN IV): contralateral superior oblique

1
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 Eye Movements

c. oculomotor (CN III): supplies the remaining four ipsilateral muscles

(medial rectus, inferior rectus, superior rectus, and inferior oblique)
- distinct columns of motor neurons in the oculomotor complex
supplies each of these four extraocular muscles (a separate pool
of motor neurons also innervates levator muscles of the eyelid)
- also remember that the Edinger-Westphal component supplies
preganglionic parasympathetic innervation to the constrictor
muscles of the iris
C. types of eye movements
1. conjugate eye movements: eyes moves together in the same direction
a. saccades
- rapid movements of the eye that abruptly change the point of
fixation (see Figure 20.4)
- can be voluntary, but most are involuntary
- after decision to saccade (or onset of a target), there is an
obligatory delay of ~200 msec before the onset of movement
- movement is “ballistic” (sudden forceful motion, without
ongoing visual guidance toward target)
- during a movement, visual information is suppressed from
perception (demonstrate this fact for yourself!)
b. smooth pursuit movements
- much slower eye movements designed to track a moving
stimulus (see Figure 20.5)
- voluntary, (usually) requiring a moving target
c. optokinetic movements
- movements of the eyes to compensate for large-scale motion of
the visual field
- operate at low stimulus frequencies when vestibulo-ocular gain
is much less than 1 (see Figure 20.6)
- very large scale motion patterns (e.g., waiting at a railroad
crossing for a train to pass) may induce optokinetic nystagmus:
- smooth pursuit movement to track a stimulus to the
limit of ocular rotation (movement in the direction of
stimulus motion)
- saccade to acquire a new element of the visual scene
for fixation (movement opposite the direction of
stimulus motion)
d. vestibulo-ocular movements (see previous tutorial on “Vestibular
System – Central Processing”)

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 Eye Movements

i. in brief, rotational movements of the head induce eye

movements opposite to the direction of rotation, thus
allowing maintained visual fixation of both eyes
2. disconjugate eye movements: eyes move in opposite directions
a. vergence movements
- eyes rotate inward (convergence) or outward (divergence) so
that the lines of fixation intersect on ‘near’ or ‘far’ visual
targets, respectively (see Figure 12.14)
- recall that along with vergence movements, accommodation of
the lens and adjustments of pupillary diameter are reflexively
yoked when fixation shifts from near to far, and vice versa
D. neural control of eye movements
1. amplitude of movement
a. encoded by duration of action potential firing in the appropriate lower
motor neurons (see Figure 20.7)
b. when eye is moved in the opposite direction, the same lower motor
neurons become transiently silent (i.e., inhibited)
2. direction of movement
a. specified by which eye muscles are activated
b. horizontal and vertical eye movements are coordinated by two “gaze
centers” in the brainstem reticular formation (see Figure 20.8)
- these “centers” are sets of highly interconnected interneurons
whose output is directed toward lower motor neurons
- horizontal gaze center (paramedian pontine reticular
formation): coordinates horizontal eye movements
- vertical gaze center (rostral interstitial nucleus in the midbrain):
coordinates vertical eye movements
- activation of both gaze centers produces oblique movements
3. “upper motor neuronal control” of saccades
a. horizontal and vertical gaze centers are influenced mainly by two
sources of descending control: the superior colliculus and the frontal
eye field (Brodmann’s Area 8)
- neurons in both structures fire just prior to making a saccade
- both structures contain a “motor map” so that activation of a
discrete site produces a saccade in a specific direction for a
specific distance in the contralateral visual hemifield
- both structures contain a “sensory map” that represents visual
space

3
 Eye Movements

b. role of superior colliculus

- in the superior colliculus, certain ganglion cells in the retina
provide direct input that is retinotopically mapped
- the sensory map is in register with a deeper map of “motor
error” that generates a shift in gaze direction
- the saccade related burst neurons, however, are not laid out in
a retinotopic map, but in a map of motor error (see Figures 20.9
and 20.10)
- the superior colliculus also contains systematic representations
of the body surface (via the anterolateral system) and auditory
space (via the inferior colliculus)
- in a similar manner, somatic sensory or acoustic stimuli may
lead to a saccade toward the source of the stimulus (a particular
location on the body surface or in the environment)
c. role of frontal eye field
- parts of the parietal or dorsal visual stream (“where” stream)
project to Area 8 and provide a visuotopic map, but the map is
less precise than in the superior colliculus
- nevertheless, activation of a particular column of neurons in the
frontal eye field drives a saccade to the location in contralateral
visual space represented by that same column of cells
- the frontal eye field projects directly to the (contralateral) gaze
centers in the brainstem and indirectly via projections to the
(ipsilateral) superior colliculus (see Figure 20.11)
d. damage to one or the other structure produces only transient deficits in
saccadic eye movements; this suggests that both are involved in
specifying saccadic behavior
e. upper motor neurons in the frontal eye fields and superior colliculus are
modulated by neural circuits in the basal ganglia and cerebellum
i. basal ganglia: involved in the initiation of appropriate saccadic
behavior and suppression of inappropriate saccades
ii. cerebellum: coordination of ongoing saccadic activity and
adjustment of gain as needed (sensory-motor learning)

4
 Eye Movements

STUDY QUESTION
Q1. When looking up into the night sky (while standing), a bolt of lightning struck somewhere off in
the far distance to your right and you quickly turn to look at the lightning. What just happened
in your brainstem?
A. The left superior colliculus directed a shift of your gaze to the distant right side of your visual
field, in the direction of the lightning strike.
B. The left frontal eye field directed a shift of your gaze to the distant right side of your visual
field, in the direction of the lightning strike.
C. Your left abducens nucleus and right oculomotor nucleus were coordinated to fire a burst of
action potentials in functional synergy.

5
 Corticospinal and Corticobulbar Pathways

Medical Neuroscience | Tutorial Notes

Corticospinal and Corticobulbar Pathways

MAP TO NEUROSCIENCE CORE CONCEPTS1

NCC1. The brain is the body's most complex organ.
NCC3. Genetically determined circuits are the foundation of the nervous system.
NCC4. Life experiences change the nervous system.

LEARNING OBJECTIVES
After study of today’s learning, the student will:
1. Characterize the organization of the corticospinal pathway from cortex to lower motor circuits in
the spinal cord.
2. Characterize the organization of the corticobulbar pathway from cortex to lower motor circuits in
the brainstem.
3. Recognize components of the corticospinal and corticobulbar pathways in the hemispheres,
brainstem and spinal cord.
4. Sketch the corticospinal and corticobulbar pathways from cortex to lower motor circuits for
volitional movement.

TUTORIAL NARRATIVE

Introduction
The goal of this tutorial is to review the organization of the pathways by which the upper motor neurons of the
motor cortex governs the lower motor neuronal circuits of the spinal cord and brainstem. The
neuroanatomical organization of these pathways is covered here. The more detailed account of their
neurophysiological roles in motor control is provided in prior tutorials in Unit 4, and in Purves et al.,
Neuroscience 5th Ed.2, Chapters 16-17 (Sinauer Assoc., Inc.). It is important for your understanding of
neurological deficits seen in the clinic to know where these pathways travel relative to the somatic sensory
pathways and to other structures (including the cranial nerve nuclei) in the brain and spinal cord.

Descending pathways to the spinal cord

The corticospinal and corticobulbar pathways are illustrated in Figures 1 and 2. Neurons in layer V of the motor
cortex give rise to axons that descend through the internal capsule, the cerebral peduncle and the medullary
pyramids to the caudal end of the medulla where most of them cross in the pyramidal decussation. These
crossed fibers descend through the lateral corticospinal tract to terminate on motor neurons and

1
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brain and nervous system, the most complex living structure known in the universe.
2 th
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1
 Corticospinal and Corticobulbar Pathways

interneurons in the lateral aspect of the ventral horn. A small number of fibers do not cross in the pyramids
but remain on the same side. These axons form the anterior corticospinal tract and innervate the medial
aspects of the ventral horn bilaterally.
Descending cortical axons that innervate the cranial nerve motor nuclei for the muscles of the face and head
are known as the corticobulbar tract3. Most of these axons innervate bilaterally premotor interneurons
associated with brainstem reticular formation. The interneurons of the reticular formation, in turn, supply the
motor nuclei. Some of the cranial nerve motor nuclei also receive direct bilateral input from the motor cortex.
The consequence of the bilateral corticobulbar innervation is that damage to the fibers on only one side does
not result in dramatic deficits in function. There are three notable exceptions to the pattern of symmetrical,
bilateral cortical innervation of the local circuits controlling cranial nerve motor nuclei. For each of these motor
nuclei, corticobulbar inputs arise from both cerebral hemispheres, but there is some bias in favor of inputs
from the contralateral motor cortex:
1) the hypoglossal nucleus;
2) the trigeminal motor nucleus;
3) the part of the facial motor nucleus that innervates the lower face. (The part of the facial motor
nucleus that innervates the upper face is innervated bilaterally)4.
Essentially, functions involving muscles of the face that may be performed unilaterally (i.e., on one side of the
face, such as pushing the tongue against one cheek, biting on one side with the lateral dentition, or raising one
corner of the mouth) are governed by upper motor neuronal control signals from the contralateral motor
cortex.
There are other important descending pathways to the spinal cord. The vestibulospinal and reticulospinal
pathways are the most important, providing descending fibers from the vestibular nuclei and the reticular
formation, respectively, that innervate lower motor neurons located medially in the spinal cord. You may also
learn about a “tectospinal” pathway from the superior colliculus to the cervical spinal cord, but most of the
descending output from the superior colliculus appears to be mediated via indirect connections through
reticulospinal projections. Here’s what’s important to know about these brainstem-to-spinal cord pathways:
 vestibulospinal tracts—feedback adjustments of posture in response to head movements and
disturbances of postural stability
 reticulospinal tract—feedforward adjustments of posture that anticipate instability associated with
voluntary movements
 tectospinal tract (mediated by projections to reticular formation and reticulospinal projections)—
feedback adjustments of head and neck posture that support a change in direction of gaze

3
A note about this term, “corticobulbar”. The brainstem has a shape somewhat resembling a bulb, especially when one considers the
shape of the pons. Some authors use this term “corticobulbar” to refer to all projections from cortex that terminate in the brainstem,
including the massive input to the pontine gray matter that we considered when we discussed input to the cerebellum via the middle
cerebellar peduncles. However, for our purposes, the term “corticobulbar” will be used to refer to just those cortical projections that
innervate circuits associated with cranial nerve nuclei in each division of the brainstem. We will use the term “corticopontine” to
refer to those cortical axons that terminate among the pontine nuclei in the base of the pons.
4 th
See Box 17A in Neuroscience, 5 Ed. for a detailed explanation of this pattern of corticobulbar innervation. The differential supply of
corticobulbar inputs to these two parts of the facial motor nucleus is why it is important to test the lower face and the upper face
separately in a neurological examination.

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 Corticospinal and Corticobulbar Pathways

Figure 1. Diagram of the corticospinal and corticobulbar tracts. Most of the corticospinal fibers cross in the pyramidal
decussation to form the lateral corticospinal tract. A small percentage of the fibers in the medullary pyramids do not
cross in the decussation. These form the anterior corticospinal tract. Some of these fibers ultimately cross the midline
lower in the spinal cord (not shown). Descending fibers that innervate the cranial nerve motor nuclei are known as
corticobulbar fibers. Unlike the corticospinal tract, which is mostly crossed, most of the corticobulbar fibers give rise
to bilateral innervation, as noted in the text. On this diagram, only the corticobulbar fibers that innervate the
contralateral motor nucleus of the seventh nerve are illustrated. (Illustration by N.B. Cant; cf. Figure 17.4 in
Neuroscience, 5th Ed., Sinauer Assoc., Inc.)

3
 Corticospinal and Corticobulbar Pathways

Midbrain
corticospinal
fibers
corticobulbar
fibers
Cerebral peduncle

Middle medulla
Middle pons
Medullary pyramid
Descending corticobulbar &
corticospinal fibers
Lateral
corticospinal
tract

Cervical spinal cord

Caudal medulla Pyramidal decussation Anterior (ventral)
(crossing of the corticospinal projection) corticospinal tract

4
 Corticospinal and Corticobulbar Pathways

Figure 2. (previous page) Sections through the spinal cord and brainstem with components of the descending
corticospinal and corticobulbar pathways labeled. Note the approximate locations of these pathways in the cerebral
peduncle (see midbrain section). It is important to understand the location of the motor tracts with respect to the
somatic sensory tracts considered in Unit 3. (sections from Sylvius4)

There are about 20 million axons in the each cerebral peduncle, but only 1 million
axons (more or less) in each medullary pyramid. (So please don’t refer to the cerebral
peduncle as the “corticospinal tract.”) This means, obviously, that about 95% of the
axons in the cerebral peduncle do not terminate in the spinal cord. The largest
component of the cerebral peduncle is the “corticopontine” projection, which is the
input from the cerebral cortex to the scattered nuclei in the base of the pons that
relay cortical signals into the cerebellum. Accordingly, there are also about 20 million
axons in each middle cerebellar peduncle.

STUDY QUESTIONS
Q1. Where would you find most of the synapses made by axons in one medullary pyramid?
A. ipsilateral motor cortex
B. contralateral motor cortex
C. contralateral ventral horn
D. ipsilateral ventral horn
E. contralateral dorsal horn
F. ipsilateral dorsal horn

Q2. Damage to one medullary pyramid would impact which “activity of daily living” most significantly?
A. writing using the contralateral hand
B. writing using the ipsilateral hand
C. pushing open a door with the contralateral hand
D. pushing open a door with the ipsilateral hand
E. kicking a ball with the contralateral foot
F. kicking a ball with the ipsilateral foot
G. walking
H. jumping

Q3. What cranial nerve innervates the muscles of facial expression?

A. CN III
B. CN V
C. CN VII
D. CN IX

5
 Corticospinal and Corticobulbar Pathways

Q4. Where would you find the facial motor nucleus?

A. thalamus
B. midbrain
C. pons
D. medulla oblongata

6
 Visceral Motor System—Functional/Anatomical Divisions

Medical Neuroscience | Tutorial Notes

Visceral Motor System—Functional/Anatomical Divisions

MAP TO NEUROSCIENCE CORE CONCEPTS1

NCC1. The brain is the body's most complex organ.
NCC3. Genetically determined circuits are the foundation of the nervous system.

LEARNING OBJECTIVES
After study of the assigned learning materials, the student will:
A. Describe the anatomical organization of the sympathetic and parasympathetic divisions of the
visceral motor system, including the sources of preganglionic innervation and the location of
postganglionic visceral motor neurons.
B. Characterize the major functions of the sympathetic and parasympathetic divisions of the
visceral motor system.
C. Identify and discuss the neural centers in the CNS that regulate the outflow of activity in the
preganglionic fibers of the visceral motor system.

TUTORIAL OUTLINE

I. Introduction
A. maintains the internal state of the body (homeostasis) and promotes changes
(allostasis) by regulating the activity of visceral organs, glands and blood vessels
B. divisions
1. three peripheral structural/functional divisions
a. sympathetic & parasympathetic divisions
i. two-neuron chains that connect CNS to peripheral effectors
ii. sympathetic division organizes involuntary responses that
prepare the body for exertion (e.g., “fight or flight”)
iii. parasympathetic division organizes involuntary activities of the
viscera in a state of relaxation, when there is a need to
replenish bodily reserves (e.g., “rest and digest” conditions)
b. enteric nervous system

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 Visceral Motor System—Functional/Anatomical Divisions

a. largely autonomous nervous system located in the walls of the

gastrointestinal tract that functions to regulate motility along
the tract, secretion, and absorption across the gut epithelium
b. involves a large number of neurons that coordinate the activity
of two neural networks in the wall of the gut
i. myenteric plexus: regulates the musculature of the gut
ii. submucus plexus: monitors chemical composition of the
lumen and regulates glandular secretions
c. capable of independent patterns of neuromuscular activity, but
is influenced by activities of sympathetic and parasympathetic
divisions, as well as circulating hormones
II. Visceral Motor Efferents & Afferents
A. efferent limb (review relevant notes from PT602)
1. sympathetic division (see Figure 21.12)
a. preganglionic neurons are arranged in the intermediolateral cell
column of the thoracic/upper lumbar spinal cord (Figure 21.2)
(i) most preganglionic neurons (which may be considered as
‘premotor’ interneurons) project only a very short distance to
the paravertebral ganglia (or sympathetic chain ganglia)
(ii) some preganglionic neurons project a longer distance to reach
prevertebral sympathetic ganglia (e.g., superior and inferior
mesenteric ganglia, pelvic plexus)
(iii) in addition, some preganglionic axons innervate the adrenal
medulla, which is considered a special sympathetic ganglion
modified for endocrine function (release of catecholamines)
(iv) use acetylcholine, which binds to nicotinic (ionotropic) and
muscarinic (metabotropic) receptors on ganglionic neurons
b. postganglionic neurons in the paravertebral and prevertebral ganglia
directly innervate the smooth muscle of blood vessels and glands in the
viscera, reproductive organs and skin, and the cardiac muscle and
pacemaker nodes of the heart
(i) postganglionic axons travel with virtually every peripheral nerve
of the body to reach their widely distributed targets
(ii) most use norepinephrine, which binds to alpha and beta
adrenergic (metabotropic) receptors
c. functional considerations
(i) generally allow body to make maximum use of its resources in
stressful or otherwise threatening circumstances

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 Visceral Motor System—Functional/Anatomical Divisions

(ii) there is always some tonic activity in postganglionic

sympathetic fibers
(iii) sympathetic control of effector systems can be graded
(iv) many sympathetic reflexes operate independently
2. parasympathetic division (see Figure 21.1)
a. preganglionic neurons are restricted to certain cranial nerve nuclei and
the intermediate gray matter of the sacral cord (Figure 21.3)
(i) cranial nerve nuclei: Edinger-Westfall nucleus (midbrain),
superior & inferior salivatory nuclei (pons & medulla), and
nucleus ambiguus & dorsal motor nucleus of vagus (medulla)
(ii) sacral preganglionic innervation arises from neurons in the
lateral portion of the intermediate gray matter
(iii) preganglionic axons travel a long distance to innervate
parasympathetic ganglia in or very close to end organs
(iv) use acetylcholine (nicotinic & muscarinic effects)
b. postganglionic neurons in the parasympathetic ganglia directly
innervate the smooth muscle of the eyes, viscera and reproductive
organs, cardiac muscle and the glands of the head
(i) since neurons are already in or near end targets, their axons
travel a very short distance to innervate peripheral tissues
(ii) use acetylcholine
c. functional considerations
(i) generally opposed to sympathetic activity: increases reserves
when conditions allow for “rest and digest” (see Figure 21.1)
(ii) parasympathetic control of effector systems can be graded (not
all-or-none) and many reflexes operate independently
B. afferent limb (see Figure 21.5)
1. sensory receptors
a. mechanoreceptors: pressure receptors in ventricles, atria and carotid
arteries (baroreceptors), and lungs; and stretch receptors that respond
to distension of the veins, bladder or gastrointestinal tract
b. chemoreceptors: sensitive to chemical concentrations in the blood;
specialized cells in the aortic and carotid bodies (oxygen), medulla (pH,
carbon dioxide), and hypothalamus (blood glucose, certain ions)
c. nociceptors: sensitive to noxious stretch, ischemia, irritating chemicals
in the visceral walls and walls of arteries
d. thermoreceptors: sensitive to changes in internal (hypothalamus) or
external temperature (skin)

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 Visceral Motor System—Functional/Anatomical Divisions

2. afferent pathways
a. afferent axons enter the CNS via two routes (roots)
(i) dorsal roots of the spinal cord
- axons terminate in intermediate gray matter
- target efferent neurons involved in segmental reflexes
- other targets are second order neurons that project to
brainstem and thalamus as part of the anterolateral
system; one important brainstem target is the nucleus
of the solitary tract (see Figure 21.5 & 21.6)
- some second order neurons also receive input from
superficial (e.g., cutaneous) nociceptors; thus, referred
pain is common with activation of visceral sensory
nociceptors (see Box 10B)
- other nociceptive second order neurons project through
the dorsal columns to the dorsal column nuclei (see Box
10C); therefore, dorsal column nuclei may also be a site
for the genesis of referred pain
(ii) cranial nerve roots
- sensory axons enter brainstem via cranial nerves IX
(glossopharyngeal) and X (vagus)
- project to caudal half of the nucleus of the solitary tract,
which integrates visceral sensorimotor function
- nucleus of the solitary tract sends axons to visceral
motor control centers in the reticular formation,
periaqueductal gray, and higher integrative centers in
the hypothalamus and limbic forebrain (via the
parabrachial nucleus and thalamus)
3. thus, visceral sensory inputs drive local reflexes that govern ongoing visceral
function and provide signals to a higher “central autonomic network” (see
Figure 21.5 & 21.7)
4. several structures in the forebrain and have an important role in the regulation
of homeostasis/allostasis; these include the amygdala, orbital and medial parts
of the prefrontal cortex, insular cortex, and the hypothalamus (see Figure 21.5
& 21.7); together they constitute a central autonomic network

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 Visceral Motor System—Functional/Anatomical Divisions

STUDY QUESTION
Suppose you are like me and you have great difficulty controlling your “nerves” when about to perform
music (or dance, theatre, etc., whatever performance art form appeals to you). At such moments, what
do you think is happening in your “central autonomic network”?
A. Activity is dramatically increasing in the neural networks that promote parasympathetic visceral
motor outflow.
B. Activity is dramatically increasing in the neural networks that promote sympathetic visceral
motor outflow.
C. Activity is dramatically increasing in neural networks that promote enteric secretions and
motility.

5
 Visceral Motor System—Hypothalamus

Medical Neuroscience | Tutorial Notes

Visceral Motor System—Hypothalamus

MAP TO NEUROSCIENCE CORE CONCEPTS1

NCC1. The brain is the body's most complex organ.
NCC3. Genetically determined circuits are the foundation of the nervous system.

LEARNING OBJECTIVES
After study of the assigned learning materials, the student will:
1. Describe the organization of the hypothalamus and identify several functions associated with
key hypothalamic nuclei.

TUTORIAL OUTLINE

I. Central control of visceral motor system

A. several structures in the forebrain and have an important role in the regulation of
homeostasis/allostasis; these include the amygdala, orbital and medial parts of the
prefrontal cortex, insular cortex, and the hypothalamus (see Figure 21.52 & 21.7);
together they constitute a central autonomic network
B. hypothalamus (Box 21A)
1. comprises a large number of distinct nuclei that subserve a broad range of
integrative functions
2. overview of connections (see Figure 21.7)
a. the hypothalamus is highly interconnected with the limbic forebrain,
especially the amygdala, parts of the hippocampal formation and
orbital-medial divisions of the prefrontal cortex
b. major outflow is directed toward integrative centers in the brainstem;
most importantly, the periaqueductal gray (midbrain) and the reticular
formation (pons and medulla)
4. overview of function
a. hypothalamus regulates five basic functions:
i. controls blood pressure and electrolyte balance

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 Visceral Motor System—Hypothalamus

ii. regulates body temperature

iii. controls energy metabolism
iv. regulates reproductive activity
v. controls emergency responses
b. basic mechanisms of regulation:
i. receives sensory and contextual information
ii. compares sensory feedback with biologic set-points
iii. activates visceral motor, endocrine and somatic motor systems
to restore homeostasis or respond to crisis conditions (promote
allostasis)
3. the nuclei of the hypothalamus are diverse anatomically and functionally (see
Box 21A for an account of several interesting examples of hypothalamic nuclei
and their functions)
a. periventricular zone
i. arcuate and periventricular nuclei:
- scattered cells that secrete releasing or inhibiting factors
into the portal circulation
- these factors modulate the production of hormones in the
anterior pituitary
b. medial zone
i. paraventricular & supraoptic nuclei:
- send axons into posterior pituitary where they secrete
oxytocin and vasopressin (anti-diuretic hormone) into the
systemic circulation
- paraventricular nucleus sends axons that descend to
visceral motor control centers in the brainstem (reticular
formation, periaqueductal gray) and spinal cord
(intermediolateral cell column)
ii. medial preoptic nucleus: sexual behavior, sexuality (sexual
identity/orientation) and other motivational states
iii. suprachiasmatic nucleus: receives retinal input and entrains
circadian rhythms to cycles of light and dark
iv. dorsomedial & ventromedial nuclei: receive heavy input from
amygdala and orbital-medial prefrontal cerebral cortex
- reproductive & parenting behavior
- feeding behavior (target of leptin: hormone that provides
feedback regulation of food intake)
- water balance & thermoregulation

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 Visceral Motor System—Hypothalamus

c. lateral zone
I. loose collection of cells (not really nuclei) that can be
considered a rostral extension of the reticular formation of the
midbrain tegmentum
II. involved in feeding behaviors, arousal and attention
III. contains major efferent fiber bundle for hypothalamic control of
brainstem and spinal cord centers

STUDY QUESTIONS
Q1. Which of the following statements DOES NOT characterize a function of hypothalamic nuclei?
A. Hypothalamic nuclei are involved in the regulation of visceral motor preganglionic
neurons in the brainstem and spinal cord.
B. Hypothalamic nuclei are involved in the regulation of the secretion of hormones in the
anterior pituitary gland.
C. Hypothalamic nuclei are involved in the regulation of the secretion of hormones in the
posterior pituitary gland.
D. Hypothalamic nuclei are involved in the regulation of circadian rhythms.
E. Hypothalamic nuclei are involved in the relay of sensory information from second order
neurons in the spinal cord and brainstem to primary sensory areas in the cerebral
cortex.
F. Hypothalamic nuclei are involved in the expression of sexual behavior and sexual
orientation.

Q2. Suppose you are examining a patient who presents with left-sided Horner’s syndrome. You
recall learning about this condition in Medical Neuroscience, and you remember that damage of
descending projections from the hypothalamus to the sympathetic preganglionic neurons in the
intermediolateral cell column may be involved. What would you expect to see upon physical
examination?
A. The left pupil is larger than the right pupil.
B. The left side of the face feels cold to the touch, relative to the right side of the face.
C. The patient will be hyperventilating.
D. The patient’s heart will be racing (in tachycardia).
E. The right pupil is larger than the left pupil.
F. The left side of the face is noticeably sweaty, but the right side is dry.
G. The left globe (eyeball) seems to be protruding outward from a normal neutral position
in the orbit.

3
 Visceral Motor System—Micturition

Medical Neuroscience | Tutorial Notes

Visceral Motor System—Micturition

MAP TO NEUROSCIENCE CORE CONCEPTS1

NCC1. The brain is the body's most complex organ.
NCC3. Genetically determined circuits are the foundation of the nervous system.

LEARNING OBJECTIVES
After study of the assigned learning materials, the student will:
1. Discuss the interplay among the sympathetic and parasympathetic divisions of the visceral
motor system and the volitional somatic motor system in the control of micturition (urination;
voiding urine).

TUTORIAL OUTLINE

I. Control of micturition (urination; voiding urine): an example of visceral motor activity and the
coordination of volitional and non-volitional motor systems (see Figure 21.92)
A. innervation
1. sensory afferents (sense bladder filling)
a. stretch receptors in bladder wall (and spindle afferents in striated
urethral sphincter) sense distension of the bladder and relay signals to
the intermediate gray of the sacral spinal cord
b. afferents synapse on cells in the ventral horn that control the external
(striated) sphincter (not illustrated in Figure 21.9)
c. afferents also synapse on second order (anterolateral system) neurons
that project to the periaqueductal gray, “micturition centers” in the
reticular formation and the nucleus of the solitary tract
2. sympathetic innervation (promotes filling of bladder)
a. postganglionic fibers innervate the smooth muscle of the bladder and
the internal urethral sphincter
b. sympathetic outflow relaxes the smooth muscle of the bladder and
closes the internal urethral sphincter, which allows the bladder to fill
3. parasympathetic innervation (promotes emptying of bladder)

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 Visceral Motor System—Micturition

a. preganglionic fibers from the sacral cord innervate peripheral ganglia

that innervate the bladder wall and cause contraction
4. somatic motor innervation (prevents emptying of bladder)
a. alpha motor neurons in the ventral horn of the sacral cord innervate
striated muscle of the external sphincter, causing it to contract
B. micturition
1. when the bladder is full, afferent activity causes an increase in parasympathetic
tone and a decrease in sympathetic tone (internal sphincter muscle relax,
smooth muscle in the bladder wall contracts), but ongoing contraction of the
external sphincter prevents micturition
2. under the appropriate circumstances (usually, hopefully!), descending inputs
coordinate an increase in parasympathetic tone, while simultaneously
decreasing the activity of relevant alpha motor neurons in the sacral cord
a. involves the periaqueductal gray and inputs from pontine micturition
“centers” in the reticular formation
b. these brainstem centers are supervised by the anterior hypothalamus,
which receives input from amygdala and medial prefrontal cortex
3. in the absence of descending control, autonomic reflex control may be
preserved in the spinal cord; but reflex activity is insufficient to provide fully
adequate control over voiding (urinary tract infections are common)

STUDY QUESTION
Which of the following changes in neural activity promotes voiding urine?
A. an increase in sympathetic activity and a decrease in parasympathetic activity
B. a concurrent increase in both sympathetic and parasympathetic activity
C. a concurrent decrease in both sympathetic and parasympathetic activity
D. a decrease in sympathetic activity and an increase in parasympathetic activity
E. an increase in somatic motor outflow to the external striated sphincter muscle

2
 Embryological Subdivisions of the Human CNS

Medical Neuroscience | Tutorial Notes

Embryological Subdivisions of the Human CNS

MAP TO NEUROSCIENCE CORE CONCEPTS1

NCC1. The brain is the body's most complex organ.

LEARNING OBJECTIVES
After study of the assigned learning materials, the student will:
1. Identify each of the major subdivisions of the adult nervous system, and relate them to their
embryological precursors and associated ventricular spaces.

NARRATIVE
by Leonard E. WHITE and Nell B. CANT
Duke Institute for Brain Sciences
Department of Neurobiology
Duke University School of Medicine

Introduction
The fundamental divisions of the brain and spinal cord are easier to appreciate if you understand their
embryological derivations. This is just one helpful means of organizing your knowledge about the central
nervous system (CNS). Thus, the human CNS—as in all other vertebrate species—is derived from four
basic embryological formations: the prosencephalon (forebrain), the mesencephalon (midbrain), the
rhombencephalon (hindbrain), and the elongated spinal cord. The embryonic divisions of the central
nervous system give rise to adult structures as summarized in the chart below (next page). This chart
depicts the conserved relationships among the parts of the developing brain and their adult brain
derivatives, although the relatively greater growth of the cerebral hemispheres makes some of these
relations somewhat difficult to appreciate.
This tutorial a refresher on the basic parts of the human central nervous system (CNS); it is designed to
help you learn how to recognize major adult derivations of each embryological formation. Hopefully,
you are now well on your way toward learning how to locate the components of important sensory,
motor, and associational pathways in each subdivision of the central nervous system. As we begin our
studies of the Changing Brain in Unit 5 of the course, let’s recount the basic events of neuroembryology
and give you opportunity to appreciate the relation between the embryological and mature forms of the
basic parts of the human CNS.

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 Embryological Subdivisions of the Human CNS

Basic subdivisions of the mammalian brain

By the end of the first month of gestation, the neural tube closes and three swellings appear at its
cephalic end (see Figure 22.3 in Purves et al., Neuroscience, 5th Ed. 2). These will form the brain, while
the rest of the neural tube gives rise to the spinal cord. The most rostral of the three, the
prosencephalon, soon divides into two parts: the telencephalon, which gives rise to the cerebral
hemispheres, and the diencephalon, which becomes the thalamus and hypothalamus. These structures
together make up the adult forebrain.
Since the nervous system starts out as a simple tube, the lumen of the tube remains in the adult brain as
a fluid-filled space. (Consider for a moment the fact that the entire brain is formed in the walls of a
hollow tube!) This fluid-filled space, known as the ventricular system, is filled with cerebrospinal fluid
(CSF) and provides an important landmark on images of the nervous system. As the brain grows, the
shape of the central space also changes from that of a simple tube to its complex adult form. The space,
although continuous, takes different names in each of the subdivisions. Thus, the spaces inside the
hemispheres are known as the lateral ventricles, and the space inside the diencephalon is the third
ventricle. The mesencephalon, which is the middle swelling in the 4-week embryo, does not divide
further and becomes the midbrain of the adult. The space inside the midbrain is called the cerebral
aqueduct.
The rhombencephalon further divides into the metencephalon, which becomes the pons and
cerebellum, and the myelencephalon, which becomes the medulla. The neural tube caudal to these
three cephalic swellings becomes the spinal cord. The space inside the developing rhombencephalon is
called the fourth ventricle. In early postnatal life, the development of the cerebellum gives rise to three
apertures in the fourth ventricle that allow cerebrospinal fluid to exit the ventricular system and bathe
the CNS in the subarachnoid space (see below). In the embryo and young children, the opening in the
spinal cord is patent and is known as the central canal. However, it is very narrow and usually reduced
to a “potential” space with very little CSF in the adult and no continuous ventricular channel connecting
the central canal to the fourth ventricle.
Not all of the brain structures just mentioned (terms in bold) are easily seen in the accompanying video
tutorial. But you have seen them all if you viewed the full set of video tutorials in Unit 1 of the course
when we explored the major parts of the adult brain. Nevertheless, at this point, focus on learning the
relationships depicted in the chart below and their embryological origins. This will help to make
relationships among brain structures and ventricular spaces in the adult much more obvious.
To test yourself (in place of a Study Question), use the ventral view of the brain in Figure 1 and label as
many of the structures in the chart below that you can find in this brain.

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 Embryological Subdivisions of the Human CNS

STUDY QUESTION
It is sometimes said that the hippocampus is a subcortical structure. What do you think? Agree or
Disagree: the hippocampus is subcortical.
A. Agree
B. Disagree
Of course, after you respond, you should think about why you choose the answer you did and whether
or not you agree with Prof. White’s opinion of this question.

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 Embryological Subdivisions of the Human CNS

Fig. 1. The ventral surface of the brain. (Image from Sylvius4)

4
 Early Brain Development

Medical Neuroscience | Tutorial Notes

Early Brain Development

MAP TO NEUROSCIENCE CORE CONCEPTS1

NCC2. Neurons communicate using both electrical and chemical signals.
NCC3. Genetically determined circuits are the foundation of the nervous system.
NCC4. Life experiences change the nervous system.

LEARNING OBJECTIVES
After study of the assigned learning materials, the student will:
1. Characterize the events that occur during gastrulation and neurulation.
2. State the significance of induction for the initial development of the CNS.
3. Discuss the factors the guide migrating neuroblasts to their final destinations in the developing
gray matter structures of the CNS
4. Characterize the cellular mechanisms that influence the differentiation of neurons and glia in
the CNS.
5. Describe the role of apoptosis in CNS development.

TUTORIAL OUTLINE

I. Introduction
A. mechanisms of neural development
1. genetic specification: lineage-derived signals expressed via gene transcription
2. self-organization: cell-cell interactions mediated via molecular and activity
based mechanisms
3. sensorimotor experience: environmental interactions expressed later in neural
development (once sensory and motor systems become functional) and
throughout life
B. each of these basic mechanisms is subject to modification due to the consequences of
genetic mutation, disease, exposure to environmental and dietary toxins, or normal and
abnormal use (sensorimotor experience)

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 Early Brain Development

1. most major congenital malformations of the CNS occur as a result of dysfunction

in the expression of genetic specification or the cell-cell interactions that give
rise to ordered patterns of structure and connectivity in neural circuits
2. in later stages of brain development, sensorimotor experience should be
considered an important factor in neurological function/dysfunction

II. Initial Formation of the CNS

A. Gastrulation
1. invagination of the developing blastula that produces three germ layers:
a. ectoderm (outer layer): gives rise to the entire nervous system!
b. mesoderm (middle layer): forms muscle, skeleton, connective tissue,
cardiovascular and urogenital systems
c. endoderm (inner layer): forms gut and associated viscera
2. forms the notochord along the dorsal midline of the embryo from mesoderm;
this transient structure defines the midline, the plane of bilateral symmetry, and
the principle axes of the embryo (anterior-posterior; dorsal-ventral; medial-
lateral)
B. Neurulation (3-4 weeks of gestation)
1. formation of the neural plate and its subsequent folding upon itself to form the
neural tube (Figure 22.12)
a. the notochord gives rise to chemical signals that “induce” the
differentiation of neural precursor cells in the overlying ectoderm

Induction: The ability of a cell or tissue to influence the fate of

nearby cells during development by the synthesis and secretion of
chemical signals (peptide hormones) that modulate gene
expression. The specificity and precise timing of inductive signaling
is crucial for normal development.

b. this special part of the ectoderm becomes a distinct columnar

epithelium called the neural plate
2. the lateral margins of the neural plate fold inward and then seal off to form the
neural tube
a. the neural tube differentiates into the entire CNS
i. all cellular components of the CNS are derived from the
epithelium of the neural tube
ii. the lumen of the neural tube becomes the ventricular spaces of
the mature brain and spinal cord

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 Early Brain Development

b. the notochord continues to provide an inductive influence as the ventral

portion of neural tube differentiates into the floor plate (see Figure
22.2)
i. in turn, inductive signals arise from the floor plate and influence
the differentiation of neural precursor cells in the ventral parts
of the neural tube
ii. some cells in these regions eventually become the motor
neurons and interneurons of the brainstem and spinal cord
c. at the other side of the neural tube, dorsal neural precursor cells are
induced to form the roof plate, which in turn induces the formation of
sensory system neurons of the brainstem and spinal cord
d. a third special region of the neural tube, also along the dorsal midline,
differentiates into the neural crest (see Figure 22.2)
i. neural crest cells migrate away from the neural tube
ii. along the way, they are influenced by a broad spectrum of
chemical signals that determine their migratory fate and
ultimate identify
iii. neural crest progeny give rise to all the neurons and glia of the
peripheral nervous system, the neurosecretory cells of the
adrenal medulla, the neurons that constitute the enteric
nervous system, and other non-neural cells (see Figure 22.11)
e. several congenital malformations of the CNS result from a failure of the
neural tube to complete seal (e.g., spina bifida, anencephaly)

III. Formation of Major Subdivisions of the CNS (3-4 months of gestation)

A. morphological alterations of the neural tube (see Figure 22.3)
1. rapid and disproportionate cellular proliferation together with movements that
bend, fold and constrict different parts of the neural tube give rise to the major
subdivisions of the embryonic brain
2. after the initial formation of the major subdivisions of the embryonic CNS,
additional partitioning of the prosencephalon establishes the early
telencephalon, diencephalon and the optic cups, which give rise to the retina
3. similarly, the rhombencephalon partitions into the metencephalon (cerebellum
and pons) and the myelencephalon (medulla oblongata)
review the relation between structures in the adult brain and their embryological
origins; see Table A24
4. these regional changes that shape the developing neural tube are influenced by
the spatial and temporal expression patterns of homeotic genes
a. in fruit flies, homeotic genes encode DNA-binding proteins that guide
the differentiation of the embryo into distinct segments, defining the
anterior-posterior axis of the body plan (see Figure 22.4)

3
 Early Brain Development

b. similar genes, called Hox genes, have been found in mammals, including
humans
c. like homeotic genes, Hox genes encode DNA-binding proteins that
modulate the expression patterns of other genes; these proteins are
important mediators of neural induction
i. in humans, we have four clusters of Hox genes, with each on a
different chromosome
ii. their expression contributes to the cellular and molecular
processes that eventually produce differentiated regions along
the anterior-posterior axis of the developing neural tube (see
Box 22B)
B. molecular basis of neural induction
1. molecular interactions between cells (in early embryogenesis, between cells in
adjacent germ layers) that are essential for shaping regional and cellular identity
(see Figure 22.5A)
a. inductive signals are secreted by: notochord, floor plate, roof plate,
somites, specific foci within the neuroectoderm (to name a few sources)
b. inductive signals are secreted and diffuse through extracellular spaces
to act on adjacent tissues
2. examples:
a. steroid hormones: retinoic acid (RA) (see Figure 22.5B)
i. small, lipophilic molecule derived from vitamin A
ii. activates retinoid receptors, which are transcription factors that
modulate the expression of target genes
iii. RA signaling drives cellular differentiation, regulating transitions
between classes of neural stem cells
iv. excess or insufficient vitamin A (or retinoid-based medications)
can disrupt early brain morphogenesis (see Box 22C)
b. peptide hormones: fibroblast growth factor, bone morphogenetic
proteins, Wnt hormone family, and sonic hedgehog
i. bone morphogenetic proteins (BMPs) (see Figure 22.5D)
- BMPs are secreted by somites and surrounding mesodermal
tissues
- and bind to receptor serine kinases that phosphorylate
transcriptional regulators (SMADs), which in turn
translocate to the nucleus and modulate gene expression
- induce the formation of bone cells in mesoderm (hence
their name); but also they induce epidermis (skin) in
ectodermal tissue …

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 Early Brain Development

- unless they are antagonized (by Noggin and Chordin), which

then allows the ectoderm to differentiate into
neuroectoderm
- evidently, the CNS is “rescued” from becoming skin by
antagonizing BMP activity!
ii. sonic hedgehog (Shh) (see Figure 22.5G)
- important for neural tube closure
- important for establishing identity
- when present, it binds to surface receptors and promotes a
switch from transcription repressors to transcription
activators (Gli1-3) that modulate gene expression
3. inductive signaling provides a “transcriptional code” for establishing local
identity in specific regions of the developing CNS, including the forebrain (see
Figure 22.6C-D)
C. generation and differentiation of neurons and glia
1. in the adult brain, there are about 100 billion neurons (and even more neuroglial
cells)!
2. during the peak cell proliferation, the rate of neurogenesis is nearly 250,000
neurons per minute!
3. nearly all neurons are generated by the middle of the second trimester;
thereafter, only very few neurons are ever generated in the CNS! (consider the
implications for learning and memory, motor skill acquisition, neuropathology
and neural rehabilitation)
4. neuronal and glial genesis occurs in the ventricular zone
a. precursor cells divide in the ventricular zone and produce other stem
cells for many (symmetrical) mitotic cycles (see Figure 22.7)
b. after asymmetrical division, one of the two daughter cells is destined to
differentiate into a glial precursors and others into neuronal precursors,
called neuroblasts (see Figure 22.10)
c. postmitotic neuroblasts migrate away from the ventricular zone toward
a target structure, such as the developing cerebral cortex, called the
cortical plate, or remain closer to the ventricular zone to populate
subcortical gray matter (primordial basal ganglia and diencephalon)
i. many neurons in the CNS are guided to final destinations by
(presumptive) glial cells that span the distance between the
ventricular zone and the pia mater
- for the developing cortical plate, neuroblasts migrate
along radial glial cells (see Figure 22.12-13)

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 Early Brain Development

- when neuroblasts reach their final destination, they

dissociate from radial glial processes and take up
residence in a particular laminar or spatial position
- in the cortical plate, neuroblasts that will come to
populate the deeper layers are generated first and
migrate to the inner most laminae (see Figure 22.8)
- later, more superficial neuroblasts are generated and
migrate through the deeper layers to reach the outer
laminae of the developing cortical plate
- the cortical plate develops in an “inside-out” pattern
- thus, organized periods of neurogenesis are important
for the development of region-specific cell types and
axonal connections
ii. a number of congenital malformations are the result of
migration errors; event subtle errors may lead to forms of
mental retardation and cerebral palsy
iii. neuroblasts that differentiate into inhibitory interneurons are
derived from the deep ganglionic eminence and migrate
tangentially to reach their final destinations (see Box 22F)
D. how do precursor cells differentiate to produce the diverse forms of neurons and glia
that are present in the mature CNS?
1. local cell-cell interactions mediated by cell surface receptors (who a cell’s
neighbors are), many of which are those same signals that served inductive
signaling at some earlier stage in development (see Figure 22.10)
2. cell lineage—distinct histories of transcriptional regulation (who a cell’s parent
is)
E. after taking up residence in a target structure, a significant portion of the neurons
produced (roughly half in certain CNS regions) undergo apoptosis
1. programmed cell death requiring the expression of so-called “suicide genes”
whose products promote the dysfunction and dissolution of otherwise viable
cells
2. cells that undergo apoptosis are not necessarily “less fit” (this does not seem to
be a Darwinian-like developmental process)
F. in the third trimester and in early postnatal life, the neurons that survive elaborate
dendritic arbors and send out axons (the story continues in the next few tutorials)

6
 Early Brain Development

STUDY QUESTIONS
Q1. Which of the following statements about the notochord is MOST accurate?
A. The notochord is derived from the ectodermal germ layer.
B. Formation of the notochord is the principal developmental achieve of neurulation.
C. The notochord provides a migratory pathway for neural crest derivatives as they
migrate toward their final locations in the developing embryo.
D. The notochord is an important source of inductive signals that induce the formation of
the neural plate in the overlying ectoderm.
E. The spinal cord of the mature the nervous system is derived from the cells of the
embryonic notochord.

Q2. What factor or factors account for the generation of diversity among the progeny of
neuroblasts?
A. local cell-cell interactions mediated by cell surface receptors
B. the distinct histories of transcriptional regulation in the progeny
C. both cell-cell interactions and transcriptional history contribute to cellular diversity in
the developing CNS

7
 Construction of Neural Circuits

Medical Neuroscience | Tutorial Notes

Construction of Neural Circuits

MAP TO NEUROSCIENCE CORE CONCEPTS1

NCC2. Neurons communicate using both electrical and chemical signals.
NCC3. Genetically determined circuits are the foundation of the nervous system.
NCC4. Life experiences change the nervous system.

LEARNING OBJECTIVES
After study of the assigned learning materials, the student will:
1. Characterize the structure and function of growth cones.
2. Discuss the major classes of molecular signals that guide axonal growth.
3. Discuss the mechanisms of neurotrophin signaling.

TUTORIAL OUTLINE

I. Introduction
A. mechanisms of neural development
1. genetic specification: phenotypes produced by spatial and temporal patterns of
gene expression in cells derived from common precursors
2. self-organization: phenotypes produced by cell-cell interactions mediated by
endogenous patterns of activity in neural networks
3. sensorimotor experience: the modulation of endogenous neural activity by the
activation of sensory receptors during environmental interactions
B. each of these basic mechanisms is subject to modification due to the consequences of
genetic mutation, disease, exposure to environmental and dietary toxins, and normal
and abnormal sensorimotor experience

II. Genetic specification and self-organization in early brain development: axon outgrowth and
path-finding through the developing nervous system
A. molecular mechanisms establish polarity in differentiating neuroblasts

1
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 Construction of Neural Circuits

1. neurites (undifferentiated processes) extend from the cell bodies

2. a single process becomes the presumptive axon (from the apical domain of the
cell)
3. other neurites (emanating from basal domain) become dendrites
B. growing (presumptive) axons explore their environment (i.e., the extracellular matrix)
with a specialized structure at the distal tip of the axon, called a growth cone (see
Figure 23.2 & 23.32)
1. contains abundant mitochondria (to fuel their high metabolic needs), thin actin
filaments and microtubules (to allow for changes in shape), and smooth
endoplasmic reticulum (to produce large quantities of plasma membrane)
2. extend cellular processes, called lamellipodia (flat sheet-like processes) and
filopodia (elongated, finger-like processes), that sample the local environment
3. these processes rapidly appear and disappear at the leading edge of the growth
cone, as the structure responds to local cues
a. receptors and channels (TRP) on the surface of the filopodia and
lamellipodia transduce local signals from adhesion molecules in the
extracellular matrix and soluble molecules that diffuse through the
extracellular spaces (see below)
b. calcium is a key mediator of these signals modifying actin filament and
microtubule dynamics within growth cones
4. the entire growth cone is highly motile; in response to local signals, growth
cones may change their speed or direction of growth
5. at “forks in the road”, growth cones must sample the local environment and
respond with directed growth (e.g., see Boxes 23A & 23B)
C. as growth cones traverse the neural terrain of the developing nervous system, axons
grow in length by adding membrane both proximally (i.e., from the cell body end of the
axon) and distally (i.e., from the growth cone), a process called elongation

STUDY QUESTION
Q1. Which of the following projections must confront a “fork in the road” in development at which
growth cones must choose to cross the midline of the developing CNS?
A. the central axons of first-order spinal mechanosensory afferents in the spinal cord
B. the central axons of first-order trigeminal pain and temperature afferents in the
brainstem
C. spinothalamic tract axons in the ventral white commissure of the spinal cord
D. optic radiation axons in Meyer’s loop
E. axons grown from neurons in Clarke’s nucleus that are pioneering the dorsal
spinocerebellar tract

2 th
Figure references to Purves et al., Neuroscience, 5 Ed., Sinauer Assoc., Inc., 2012. [click here]

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 Construction of Neural Circuits

D. molecular signals for axon guidance

1. cell-associated molecules on the surface of cells and molecules embedded
within the extracellular matrix (see Figure 23.4)
a. general mode of operation:
(i) molecules on the surface of growth cones and axons interact
with similar (or in some instances, the same) molecules on
other cellular surfaces, and with molecules embedded in the
extracellular matrix
(ii) such molecular interactions trigger cascades of intracellular
events within the growth cone that lead to axon elongation
(iii) some of these molecules (ephrins and Eph receptors) are
important for topographic map formation, as they signal
appropriate substrata for axonal growth and synaptogenesis
(see Figure 23.7)
b. certain classes of molecules mediate interactions that stabilize the
linkages between axons and glial cells and between adjacent axonal
membranes, thus permitting the establishment of axonal tracts
(fasciculation or bundling of axons)
2. diffusible molecules
a. general mode of operation:
(i) target tissues secrete soluble molecules that diffuse into the
extracellular fluids and effect axonal growth and survival
(ii) such molecules interact with receptors on the surface of the
growth cones and trigger cascades of intracellular events that
mediate these effects
b. tropic molecules: guide growing axons toward or away from a source
(see Figure 23.5 & 23.6)
(i) chemo-attractant
(ii) chemo-repellant
c. trophic (neurotrophic) molecules
(i) promote the survival and growth of neurons and their processes
(axons and dendrites)
(ii) match innervation (numbers of efferent and afferent neurons)
with the amount of target tissue that is present in the periphery
(see Figure 23.10)
(iii) establish the appropriate degree of convergence and
divergence between neurons and their targets (see Figure 23.11
& 23.12)

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 Construction of Neural Circuits

(iv) shapes the distribution of local neuronal processes (Box 23D)

(v) the production of neurotrophins by target tissues is regulated
by patterns of neural activity
- provides the basis for activity-dependent competition
among a set of inputs that are seeking to establish
connections with the same target cell
- blocking activity in the pre- or post-synaptic element
disrupts competitive interactions
(vi) important (known) trophic factors (neurotrophins) (see Figure
23.16)
- nerve growth factor (NGF)
- brain-derived neurotrophic factor (BDNF)
- neurotrophin-3 (NT3)
- neurotrophin-4/5 (NT4/5)
(viii) neurotrophin signaling
- the selective actions of the neurotrophins arise from
interactions with different classes of surface-bound
receptors: Trk receptors and the p75 receptor
- Trk receptors (three types)
- all single, transmembrane proteins with
tyrosine kinase (trk) activity on their
cytoplasmic domain
- certain neurotrophins bind to certain types of
Trk-receptors (see Figure 23.16)
- p75 receptor
- all known neurotrophins bind to p75
- but affinity is highest for the unprocessed,
newly secreted form of neurotrophin
- neurotrophin receptors can activate a variety of second
messenger systems within target cells mediating both
local effects within a process and transcription-
dependent effects in the cell body (see Figure 23.17)
- neurotrophin signaling is implicated in a variety of
degenerative diseases of the CNS
E. synapse formation
1. begins with recognition of presumptive pre- and post-synaptic elements by
calcium-dependent cell adhesion molecules (see Figure 23.8A)

4
 Construction of Neural Circuits

2. once initial specialization is established, additional adhesion molecules from the

family of calcium-independent cell adhesion molecules, together with the
activity of ephrin ligands and their Eph receptors, induce the assembly of
presynaptic machinery for chemical neurotransmission and postsynaptic
specialization necessary to insert specific receptors and transduce chemical
signals (see Figure 23.8B-C)
a. neurexin acts to assemble the active zone in the presynaptic membrane
b. the presynaptic terminal releases neuregulin, which influences the
organization of the postsynaptic site
c. neuroligin acts to assemble postsynaptic density proteins that anchor
the transduction machinery

STUDY QUESTION
Q2. Which of the following functions is attributable to the activity of neurotrophins?
A. attract the growth of elongating axons to a certain region of the developing CNS or PNS
B. repel the growth of elongating axons to a certain region of the developing CNS or PNS
C. promote the survival and growth of neurons and their processes
D. match neural innervation with the amount of target tissue
E. establish the appropriate degree of convergence/divergence between neurons and their
targets
F. A & B are both important functions of neurotrophins
G. C, D & E are all important function of neurotrophins

5
 Modification of Neural Circuits in Early Neonatal Life

Medical Neuroscience | Tutorial Notes

Modification of Neural Circuits in Early Neonatal Life

MAP TO NEUROSCIENCE CORE CONCEPTS1

NCC4. Life experiences change the nervous system.
NCC7. The human brain endows us with a natural curiosity to understand how the world works.
NCC8. Fundamental discoveries promote healthy living and treatment of disease.

LEARNING OBJECTIVES
After study of the assigned learning materials, the student will:
1. Discuss the significance of genetic specification, self-organization and sensory experience for the
construction of neural circuits in the cerebral cortex.
2. Discuss the significance of experience for the plasticity of neural circuits in critical periods of
postnatal development.
3. State Hebb’s postulate and discuss its relevance for neural plasticity in developing and
recovering brains.

TUTORIAL OUTLINE

I. Introduction
A. mechanisms of neural development
1. genetic specification: phenotypes produced by spatial and temporal patterns of
gene expression in cells derived from common precursors
2. self-organization: phenotypes produced by cell-cell interactions mediated by
endogenous patterns of activity in neural networks
3. sensorimotor experience: the modulation of endogenous neural activity by the
activation of sensory receptors during environmental interactions
B. each of these basic mechanisms is subject to modification due to the consequences of
genetic mutation, disease, exposure to environmental and dietary toxins, and normal
and abnormal sensorimotor experience

1
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1
 Modification of Neural Circuits in Early Neonatal Life

II. Sensorimotor experience in early brain development: “precritical” circuit construction and
modification in a critical period
A. subcortical brain circuits and circuits set-up by the topographic mapping of thalamic
projections to the cerebral cortex
1. overview
a. such circuits develop in a formative (“precritical”) phase, under the
influence of genetic specification and self-organization, without the
need for sensorimotor experience
b. however, in a later (“critical period”) phase of development, such
circuits are plastic for a period of early life
2. evidence for this view has come mainly from studies of ocular dominance
columns in the visual cortex of animal models
a. ocular dominance columns are alternating patches of monocular inputs
from the lateral geniculate nucleus to cortical layer 4 (recall that
binocular interactions do not occur until layer 4 signals are passed on to
cortical layer 2/3) (see Figure 12.132 & 24.4)
b. ocular dominance column plasticity
i. ocular dominance columns develop early (in utero in primates),
even in animals (carnivores) raised in complete darkness
ii. thus, sensory experience (vision) is not needed for the
formation of these circuits
iii. however, once established in visual cortical circuitry, ocular
dominance columns are plastic in early life (see Figure 24.4-
24.7)
- a brief period of monocular vision in early life can lead to
permanent blindness (amblyopia)
- amblyopia is explained by a dramatic shift in the size of
ocular dominance columns in V1 (see Figures 24.6-24.8)
- open-eye columns expand (grow new connections)
- deprived-eye columns shrink (lose connections)
- these effects are not (usually) seen in adults
iv. ocular dominance column plasticity has been the dominant
paradigm for understanding the construction of neural circuits
within critical periods of early postnatal life; indeed, this
paradigm has been the “gold standard” for evaluating
mechanisms of neural plasticity for more than 5 decades!

2 th
Figure references to Purves et al., Neuroscience, 5 Ed., Sinauer Assoc., Inc., 2012. [click here]

2
 Modification of Neural Circuits in Early Neonatal Life

v. but does this paradigm—“precritical” period (no plasticity)

followed by critical period plasticity—apply to other cortical
circuits? (evidently, not universally)
B. intrinsic neural circuits of the cerebral cortex (beyond the input layer, layer 4)
1. more recently, developmental neuroscientists have studied the formation of
intrinsic cortical circuits (columnar circuits that compute new functional
properties within the middle and upper layers of the visual cortex), and results
suggest a more important role for experience in circuit construction
2. two important model circuits for these studies (also in visual cortex)3:
a. orientation columns: columnar circuits in the visual cortex that compute
the orientation (axis of motion) of contours in visual stimuli (Figures
12.11 & 12.12)
b. direction columns: columnar circuits in the visual cortex that compute
the direction of motion of visual stimuli
3. studies of orientation columns
a. orientation preference maps in different species share a “common
design”, with a pinwheel density of π (see Kaschube et al., 2010)
i. this strongly suggests that the neural networks in the visual
cortex that compute orientation preference self-organize
ii. essential factors are (1) activity-dependent development; and
(2) long-range connections across the developing network
b. orientation columns are present at the onset of visual experience in
animals reared normally and in animals reared in complete darkness
(White et al., 2001), as predicted by models of self-organizing cortical
networks
c. however …
i. in animals reared in darkness, orientation selectivity is weak,
indicating some benefit of normal sensory experience
ii. in animals reared with abnormal experience (through closed
eye-lids), orientation selectivity is so weak that orientation
columns are barely discernible (bad experience is worse than no
experience!)

3
If you are interested in learning more about this topic, see:
White, L.E., Coppola, D.M. & Fitzpatrick, D. The contribution of sensory experience to the maturation of orientation selectivity in ferret visual
cortex. Nature 411, 1049-1052 (2001).
Li, Y., Fitzpatrick, D. & White, L.E. The development of direction selectivity in ferret visual cortex requires early visual experience. Nature
Neuroscience 9, 676-681 (2006).
White, L.E. & Fitzpatrick D. (2007) Vision and cortical map development. Neuron 56:327-338.
Li Y, VanHooser S, Mazurek M, White LE, Fitzpatrick D (2008) Experience with moving visual stimuli drives the early development of cortical
direction selectivity. Nature 456:952-956.
Kaschube M, Schnabel M, Löwel S, Coppola DM, White LE, Wolf F (2010) Universality in the evolution of orientation columns in the visual
cortex. Science 330:1113-1116. *see also “Perspectives” article by K.D. Miller published concurrently: Science 330:1059-1060.]

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 Modification of Neural Circuits in Early Neonatal Life

d. conclusions …
i. normally, self-organization operates synergistically with
sensorimotor experience to promote full functional maturation
ii. when experience is rendered abnormal, this synergy is broken,
self-organization goes awry, and the neural circuits are
functionally impaired
- in other words, neural circuits self-organize to adapt to the
quality of the incoming sensory signals
- not only do neural circuits fail to benefit from normal
experience, they are harmed by abnormal experience
4. studies of direction columns
a. direction columns are absent at the onset of visual experience in
animals reared normally and emerge after 1-2 weeks of vision
b. direction columns fail to form in complete darkness
c. the critical period for the development of direction columns is
remarkably brief: only animals that experience vision in the first 1-2
weeks after eye-opening (neonates) develop direction columns
d. early vision drives the development of direction columns (and neuronal
direction selectivity)
i. experience with motion energy is necessary
ii. changes can happen quickly (hours)
iii. for some cells, this requires reversing an initial direction
preference
e. conclusions …
i. the neural circuits that underlie direction columns cannot self-
organize, but must be instructed (trained) by visual experience
with moving stimuli
ii. the window of opportunity for this motion training is very brief,
so early experience is critical!
C. summary
1. to understand the construction of neural circuits, we must examine multiple
circuits in the developing brain (there should be no one “gold standard”)
2. the “two-phase” (precritical then critical period) view of brain development in
early life is not adequate to account for the role of experience in the
development of intrinsic cortical circuits
3. sensorimotor experience may influence the construction of neural circuits as
soon as the brain becomes responsive to environmental signals

4
 Modification of Neural Circuits in Early Neonatal Life

4. thus, genetic specification, self-organization, and sensorimotor experience

interact (concurrently, not necessarily in sequential phases) to shape the
ongoing development and refinement of neural circuits in early life
III. Lessons learned and proposed clinical relevance
A. normal sensorimotor experience has a profound effect on the formation and
maturation of neural circuits in the cerebral cortex
B. some properties (timing-based properties like direction selectivity) may not develop
without normal experience in an early critical period
C. abnormal sensorimotor experience in early critical periods may lead to lasting functional
impairment
D. in sum, normal experience in early postnatal life is critical!

IV. Neurobiological explanations of how neural activity affects developing circuits

A. remember Hebb’s postulate
1. coordinated activity of a presynaptic terminal and a postsynaptic cell would
strengthen the synaptic connection between them
2. conversely, uncoordinated activity between synaptic partners would weaken
their synaptic connections
3. in short, “neurons that fire together, wire together”
B. principles of plasticity applied to developing cortical circuits (see Figures 24.1)
1. sensorimotor experience is an important source of spatial and temporal
structure in evoked patterns of neural activity
2. normal sensorimotor experience provides the conditions for the coordinated
synaptic activation of postsynaptic neurons
a. (presumably) satisfying the requirements for LTP in spike timing-
dependent plasticity (“pre” before “post”)
b. such activity is critical for the normal formation and maturation of
neural circuits in the cerebral cortex, especially those circuits that must
“compute” new functional properties
3. abnormal sensorimotor experience fails to provide for the coordinated
activation of pre- and post-synaptic neurons
a. (presumably) favoring LTD in spike timing-dependent plasticity (“post”
before “pre”)
b. this uncoordinated activity fails to promote full functional maturation
and may promote the formation of maladapted circuits
4. lasting change in developing cortical circuits is thought to be mediated by
neurotrophins
a. the production and release of neurotrophins is activity-dependent

5
 Modification of Neural Circuits in Early Neonatal Life

b. neurons that are connected and coordinated will strengthen their

interconnections and be nourished via the release and retrograde
activity of neurotrophins in presynaptic neurons
c. circuits that are driven by abnormal experience (connected but not
functionally coordinated) may weaken their connections; such
connections may fail to thrive being deprived of sufficient neurotrophic
support
5. in the mature CNS, the regulated secretion of neurotrophin helps to shape
neuronal connections in response to injury or adaptation to new patterns of
neural activity
a. several studies of recovering brain (in animal models of stroke or TBI)
now link BDNF activity to adaptive circuit plasticity
b. there are even emerging genomic studies in humans indicating that
variations in the BDNF gene render cortical circuits more or less
adaptive to challenges in the domains of motor learning and cognition
6. for current and future clinicians, the upshot of this tutorial is … what you do
with your patients/clients (of any age) with brain injury—the sensorimotor
experience you structure and reinforce— will modulate the production of
neurotrophins and shape plasticity in their developing/recovering brains!

STUDY QUESTION
Sadly, it is estimated that congenital cataracts are responsible for 5% to 20% of blindness in children
worldwide, and although the incidence varies from country to country, it is reasonable to estimate a
rate of 3-4 visually significant cataracts per 10,000 live births.
Q1. For babies born with a cataract in one eye, what is the major neurobiological concern, if left
untreated beyond the relevant critical period?
A. impaired formation of the optic nerve in the affected eye
B. exuberant growth of the optic nerve from the unaffected eye
C. cortical blindness (amblyopia) for signals derived from the affected eye
D. exuberant growth of the thalamocortical axons that are driven by the affected eye
E. double vision

Q2. For babies born with cataracts in both eyes, what is the major neurobiological concern, if left
untreated beyond the relevant critical period?
A. impaired orientation selectivity in the visual cortex
B. impaired direction selectivity in the visual cortex
C. impaired stereopsis in the visual cortex
D. A, B & C are all significant concerns
E. there are no time-sensitive concerns and successful treatment can be initiated at any
age

6
 The Changing Brain Across the Lifespan: Development, Repair & Regeneration

Medical Neuroscience | Tutorial Notes

The Changing Brain Across the Lifespan: Development, Repair &
Regeneration

MAP TO NEUROSCIENCE CORE CONCEPTS1

NCC4. Life experiences change the nervous system.
NCC8. Fundamental discoveries promote healthy living and treatment of disease.

LEARNING OBJECTIVES
After study of the assigned learning materials, the student will:
1. Discuss the neurobiological basis for changes in gray matter and while matter volume in the
developing human brain throughout childhood.
2. Discuss the mechanisms of regeneration of peripheral nerves following injury.
3. Discuss the mechanisms of plasticity in adult sensorimotor maps following peripheral injury.
4. Discuss the mechanisms of plasticity in adult neural circuits following central injury.
5. Discuss the evidence regarding neurogenesis in the adult CNS.

TUTORIAL OUTLINE

I. Introduction
A. mechanisms of neural development
1. genetic specification: phenotypes produced by spatial and temporal patterns of
gene expression in cells derived from common precursors
2. self-organization: phenotypes produced by cell-cell interactions mediated by
endogenous patterns of activity in neural networks
3. sensorimotor experience: the modulation of endogenous neural activity by the
activation of sensory receptors during environmental interactions
B. as development proceeds across the lifespan, these fundamental forces continue to
shape the structure of function of neural circuits—albeit with limited capacity to learn,
repair and regenerate outside of the critical periods that characterize early life

1
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 The Changing Brain Across the Lifespan: Development, Repair & Regeneration

II. Ongoing development of the human brain throughout childhood

A. commensurate with the onset and duration of many known critical periods in early life,
there is an explosive increase in synaptogenesis across the cortical mantle (see Figure
24.122)
1. in rhesus monkey (and presumably in humans):
a. there is an explosive increase in synapse formation (synaptogenesis) in
the neonatal period that continues through early childhood
b. although there is likely both synapse construction AND synapse pruning
occurring concurrently, the major developmental theme of early life is
the construction of neural circuits with a several-fold increase in the
total numbers of synaptic connections in most gray matter structures
2. presumably, the capacity to build new synaptic connections is an important
component to critical period plasticity and the rapid learning that occurs in early
life (see Figure 24.11)
3. however, the rate of synaptogenesis and/or the proper construction of
functional, adaptive neural circuits may be altered in disorders of cognition and
behavior, such as autism spectrum disorders, schizophrenia, and attention
deficit-hyperactivity disorder (ADHD)
a. autism spectrum disorder
i. there appears to be an accelerated rate of synaptogenesis in the
frontal and temporal lobes, and in the amygdala and
cerebellum, resulting in an overgrowth of neural circuits and an
early increase in overall brain size
ii. by adolescence, differences in gray matter trend toward normal
volumes
iii. however, aberrant wiring patterns of cortical and subcortical
networks are likely to persist, especially in networks subserving
social cognition and verbal and non-verbal communication
b. attention deficit-hyperactivity disorder (ADHD)
i. there appears to be decreased rate of synaptogenesis
resulting in a developmental delay in circuit construction
and an overall decrease in the thickness of cortical gray
matter, especially in the frontal and temporal lobes
B. beginning in later childhood (pre-adolescent), there is a net reduction in the numbers of
synapses in the cerebral cortex (see Figure 24.12)
1. in most cortical areas, there is 20-50% reduction in the numbers of synaptic
connections from the peak in early childhood to a stable plateau in young
adulthood

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 The Changing Brain Across the Lifespan: Development, Repair & Regeneration

2. this reduction in synaptic connections is the major factor responsible for a

reduction in the volume of gray matter in the cerebral cortex observed in the
same time frame (recall that synapses are localized to gray matter) (see Figure
24.13)
a. in ADHD, there appears to be a modest increase in the rate of gray
matter thickness reduction (see Figure 24.14)
b. consequently, cortical gray matter volumes are (on average) reduced in
adults with ADHD
C. throughout childhood and into adulthood, there is an increase in white matter volume
(see Figure 24.13B)
1. this increase likely reflects an increase in myelination of axonal pathways in the
brain; and it could also reflect an increase in the numbers of axons within
pathways
D. thereafter, overall brain size gradually decreases throughout adulthood, presumably
reflected the loss of synaptic connections, axons and myelin (see Figure 31.18)
1. however, a loss of neurons is not typical in adult aging, unless
neurodegenerative disease is manifest

III. Plasticity in sensory and motor maps

A. the organization of sensory and motor maps may be altered by damage to peripheral
nerves and/or changes in ongoing patterns of neural activity
B. the degree of plasticity is much greater during early critical periods, but some plasticity
in map structure persists into adulthood
C. in the somatic sensory cortex
1. when peripheral nerves are lesioned, central representations reorganize (see
Figures 9.14; consider also phantom limb sensations – Box 10D)
a. in the short-term, newly deafferented cortical zones become
unresponsive
b. however, over time, deafferented cortical zones become responsive to
sensory stimuli that drive adjacent regions of cortex
2. reorganization may also be seen in an intact system when patterns of neural
activity are habitually reinforced (e.g., with extensive practice or non-use) ((see
Figures 9.15)
D. in the motor cortex
1. “over training” can induce an expansion of the motor representation of the
practiced movements in the primary motor cortex
2. similar plasticity has been observed in animals recovering from brain injury (e.g.,
stroke) who were rehabilitated using specific motor sequences
E. mechanisms of circuit plasticity in the cerebral cortex

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 The Changing Brain Across the Lifespan: Development, Repair & Regeneration

1. plasticity may occur at multiple stations along a sensory or motor pathway

2. however, plasticity is understood best at the level of the cerebral cortex where
intrinsic cortical circuits are modified by experience
3. long-range horizontal connections are a likely mediator of cortical plasticity in
sensory and motor maps
a. horizontal connections span many cortical columns and interconnect
different parts of maps that are functionally synergistic
(i) normally, effects of horizontal connections are weak (or maybe
even “silent” – see Box8B)
(ii) in response to deafferentation (see below), disuse or overuse,
the synapses made by horizontal connections may become
strengthened and more effective at driving neuronal responses;
they may mediate at least the early phases of cortical
reorganization
(iii) long term consequences may involve growth of new
connections that reinforce longer lasting effects on the
structure of cortical maps

IV. Peripheral nerve regeneration

A. following damage (severing, evulsing or crushing a nerve), a sequence of events plays
out that results in partial restoration of sensory and motor function (see Figure 25.6)
1. macrophages rapidly remove myelin and axonal debris as the distal portion of
the axon degenerates
2. Schwann cells proliferate, express adhesion molecules and other growth-
promoting signals
3. the neuronal cell body expresses genes that reactivate growth programs that
allow for the formation of a growth cone and the transduction machinery that is
necessary to respond to factors produced by Schwann cells
4. regenerating axons elongate as growth cones migrate along extracellular matrix
and the relatively orderly array of Scwhann cells that guide growth cones to
their peripheral targets
5. for motor axons and some sensory afferents (e.g., Merkel cell-neurite
complexes), synapses form on target tissues using similar mechanisms that
established synaptic connectivity in development
B. however, the fidelity of regeneration is limited and full functional recovery may not be
achieved

V. Plasticity of neural circuits in response to brain injury

A. in response to brain injury (following trauma, hypoxia or the onset of
neurodegenerative disease), neuronal loss is often exacerbated by programmed cell
death and the inability to restore long axonal projections
1. fatally injured neurons die acutely or undergo apoptosis (see Figure 25.9)

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 The Changing Brain Across the Lifespan: Development, Repair & Regeneration

a. cell death may be triggered by over-activation of glutamatergic synaptic

inputs (“excitotoxicity” – see Box 6C)
b. cell death may be triggered by inflammatory mediators (cytokines), DNA
damage, loss of neurotrophic support, and other means of cellular
stress
c. whatever the trigger, lost neurons cannot be replaced via mitosis and
differentiation of neuroblasts (with few exceptions – see below)
2. in compact white matter structures, damage to long pathways in the CNS have
limited capacity to regenerate
a. glial cells respond to signals produced by damaged tissues and immune
cells that infiltrate the region of damage, and proliferate forming scars
that congest the local volume of brain tissue (see Figure 25.3B)
b. glial reactions create an environment that is “non-permissive” for the
regrowth of long axonal projections (see Figure 25.11)
c. oligodendrocytes produce signaling molecules (myelin associated
proteins) that inhibit axonal growth and elongation
B. however, in gray matter, surviving circuit elements may undergo functional and
structural plasticity; the key to recovery is the capacity of these elements to reorganize
and reshape the strength and distribution of their synaptic connections
1. cortical (and subcortical) connections may be modified by central injury; e.g.,
following stroke
a. injury to brain tissue surrounding the core of infarction will undergo a
sequence of activity-dependent changes in:
i. patterns of neural activity
ii. patterns of gene expression
iii. patterns of synapse formation and axonal outgrowth
b. changes in the patterns of gene expression (and their consequences)
often involve expression of the same genes (i.e., encoding tropic
molecules, trophic molecules, and their receptors) that were initially
induced in the early construction of neural circuits
c. thus, the plastic response of injured neural tissue likely involves the
reactivation of developmental programs
C. the capacity for neuronal regeneration (i.e., mitosis and production of new neurons) is
limited to special populations of neural stem cells close to the lateral wall of the lateral
ventricle (in the so-called “subventricular zone”) (see Figure 25.13 & 25.14)
1. these new neurons provide interneurons for local circuits in the dentate gyrus (a
component of the hippocampus)
2. despite some recent controversy, it now appears clear that few if any new
neurons contribute to neural circuits in the neocortex (see Box 25C)

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 The Changing Brain Across the Lifespan: Development, Repair & Regeneration

3. nevertheless, the addition and integration of new neurons in the dentate gyrus
may be important for neuropsychiatric disease and treatment

STUDY QUESTIONS
Q1. At roughly what age would you expect that highest density of synapses in the human cerebral
cortex?
A. third trimester of gestation
B. first 6 (postnatal) months of infancy
C. near the middle of the first decade of life
D. near the middle of the second decade of life
E. after the second decade of life

Q2. What factors contribute to the limited regenerative capacity of corticospinal tract axons
following spinal cord injury?
A. glial scar formation in damaged white matter (e.g., in the lateral column of the spinal
cord)
B. the suppression of growth promoting genes in the cell bodies of corticospinal tract
neurons
C. the expression by astrocytes of semaphorins, ephrins and slits that promote growth
cone collapse
D. the expression by oligodendrocytes of integral membrane proteins, such as NogoA,
myelin associated protein, and oligodendrocyte myelin glycoprotein, that inhibit axon
growth
E. all of the above factors contribute to the limited regenerative capacity of corticospinal
tract axons following spinal cord injury

6
 Overview of Associational Cortex

Medical Neuroscience | Tutorial Notes

Overview of Associational Cortex

MAP TO NEUROSCIENCE CORE CONCEPTS1

NCC5. Intelligence arises as the brain reasons, plans, and solves problems.
NCC7. The human brain endows us with a natural curiosity to understand how the world works.

LEARNING OBJECTIVES
After study of the assigned learning materials, the student will:
1. Characterize the behaviors and corresponding neural processes that contribute to cognition.
2. Discuss the major similarities and differences in the organization of primary cortex and
associational cortex.

TUTORIAL OUTLINE
I. Introduction to the neuroscience of cognition
A. lay-person’s definition of cognition: the process of knowing
B. neurobiological definition: the neural processes by which the brain integrates
meaningful stimuli, memory, and internal motivations producing perceptional
awareness and appropriate behavior
C. Table 1. Neural processes that contribute to cognition

Cognitive
process Metaphor / Example Neural Process
Attention cognitive “search light” modulatory influences of brainstem reticular formation,
hypothalamus and basal forebrain nuclei on thalamic and cortical
processes

Recognition finding a friend’s face in a crowd coding of feature representations in primary and higher order
sensory cortices

Integration knowing that friend integration (“association”) of disparate processing streams in

associational cortices

Planning deciding to seek out that friend processing in executive associational cortices in prefrontal cortex
of frontal lobe

Selection & Walking towards that friend and implementation of short-term and long-term plans via somatic
execution engage in conversation motor, visceral motor and emotional motor systems

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 Overview of Associational Cortex

II. Anatomy of the Associational Cortex

A. review of cortical structure and function
1. “canonical” (i.e., standard/representative) cortical microcircuit
a. the columnar circuit is the fundamental unit of processing and
computation in the complex circuitry of the cerebral cortex
b. within a cortical column, different types of excitatory and inhibitory
neurons populate distinct cellular layers
(i) the main excitatory neurons are pyramidal neurons
(ii) the inhibitory neurons are diverse morphologically and
functionally
c. each layer maintains distinct sets of inputs and outputs
(i) pyramidal neurons project:
- to other neurons in the same layer and across layers
within the local column
- to other columns in the same cortical area
- to other columns in other cortical areas, including the
corresponding area in the opposite cerebral hemisphere
- to subcortical targets (e.g., corticospinal tract neurons)
(ii) most inhibitory neurons project locally within their home layer
and column, but some do project across cortical columns within
the same area (few project to other areas; very few if any
project to the other hemisphere or subcortically)
B. distribution of associational cortex (see Figure 26.12)
1. only about 25% of the cerebral mantle is comprised of primary sensory and
motor cortex; the remaining 75% is termed associational cortex
2. with the possible exception of the occipital lobe (which is largely if not entirely
devoted to increasingly complex aspects of visual processing), all other lobes
contain associational cortex
3. as its name implies, the associational cortex integrates (or associates) different
types of inputs, some of which come from primary and higher order sensory
cortex
4. it is in the associational cortices that most of the neural processes of cognition
are carried out (together with interactions among subcortical neural centers)
C. differences between associational cortex and primary cortex (see Figure 26.4)
1. unlike primary cortices, which receive their main input from specific sensory and
motor relay nuclei of the thalamus, the associational cortex receives its most
influential input from other parts of the cortex

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 Overview of Associational Cortex

2. associational cortex does receive input from thalamus, but it arises from
thalamic nuclei (pulvinar, posterior nuclei, and mediodorsal nucleus) that are
themselves driven by highly processed “feedback” projections from the cortex
(rather than from “feedforward” sensory systems) (see also Appendix BoxA)
3. other sources of input come from brainstem modulatory systems:
a. noradrenergic cells of the locus coeruleus
b. serotonergic cells of the Raphe nuclei
c. dopaminergic cells of the ventral tegmental area)
4. and from the basal forebrain:
a. cholinergic cells in the basal nucleus of Meynert

STUDY QUESTION
Cognition is an emergent property of brain function, reflecting (as Charles Sherrington famously put it a
century ago) the integrative action of the nervous system. Nevertheless, it is useful to identify and study
distinct neurobiological mechanisms that support disparate functions that contribute to cognition.
Which cognitive process is attributable to the functions of brainstem modulatory (biogenic amine)
systems?
A. selection and execution of short and long-term plans
B. integration of disparate processing streams
C. recognition and coding of salient features
D. attentional modulation of sensory processing
E. planning appropriate behaviors

3
 Associational Cortex of the Parietal Lobe

Medical Neuroscience | Tutorial Notes

Associational Cortex of the Parietal Lobe

MAP TO NEUROSCIENCE CORE CONCEPTS1

NCC5. Intelligence arises as the brain reasons, plans, and solves problems.
NCC7. The human brain endows us with a natural curiosity to understand how the world works.

LEARNING OBJECTIVES
After study of the assigned learning materials, the student will:
1. Discuss the major functions that are localized to the associational cortex of the parietal lobe.

TUTORIAL OUTLINE

I. Parietal associational cortex

A. anatomical location:
1. cortex posterior to the primary somatic sensory cortex in the postcentral gyrus
2. superior parietal lobule: cortex medial to the intraparietal sulcus, including the
medial cortex in the precuneus gyrus
3. inferior parietal lobule: cortex lateral to the intraparietal sulcus, including the
supramarginal and angular gyri
B. function
1. involved in directing attention toward perceptual cues in the environment
(recall that the posterior parietal lobe processes “Where” visual signals)
2. attentional modulation of sensory processing
a. attentional mechanisms lead to increases in the firing rates of posterior
parietal neurons that sustain attention in lower-order sensory cortex
(see Figure 26.92)
i. attentional modulation of sensory responses in primary sensory
cortex is likely dependent upon cortico-cortical feedback from
posterior parietal cortex (see Figure 26.10)

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 Associational Cortex of the Parietal Lobe

b. thus, “paying attention” (or not), likely reflects the depth of modulation
of ongoing activity in sensory cortex by sensory stimuli
i. strong modulations of sensory activity are associated with
improved perceptual and behavior performance
ii. weaker modulations are associated with increased frequency of
perceptual “failures”
3. cortical asymmetry of attention
a. the left parietal lobe is mainly concerned with the right hemifield, while
the right parietal lobe is engaged by stimuli in either hemifield (see
Figure 26.6B)
b. thus, lesions of the right parietal lobe tend to produce profound deficits
in attention directed toward the left hemifield, termed contralateral
neglect syndrome, while lesions of the left parietal lobe produce few
attentional deficits (see Figure 26.6A)
i. such patients display an inability to attend to objects, or even
their own body, on the left side of the midline
ii. this attentional deficit may present without impairments in
visual function, somatic sensation or motor ability
4. posterior parietal cortex is involved in maintaining a neural representation of
self; which is sometimes referred to as the body image or body schema
a. parietal associational cortex builds a model of self relative to its
component parts (musculoskeletal units) and to the external
environment

STUDY QUESTION
A colleague described a patient that he studied who had a cortical stroke, which resulted in limb
weakness and a bizarre denial of impairment (anosognosia). Which limb was (most likely) impaired?
*Hint: this women’s anosognosia can be considered an extreme form of hemineglect.]
A. left lower extremity
B. right lower extremity
C. left upper extremity
D. right upper extremity
E. bilateral weakness of the lower extremities

2
 Associational Cortex of the Temporal Lobe

Medical Neuroscience | Tutorial Notes

Associational Cortex of the Temporal Lobe

MAP TO NEUROSCIENCE CORE CONCEPTS1

NCC5. Intelligence arises as the brain reasons, plans, and solves problems.
NCC7. The human brain endows us with a natural curiosity to understand how the world works.

LEARNING OBJECTIVES
After study of the assigned learning materials, the student will:
1. Discuss the major functions that are localized to the associational cortex of the temporal lobe.
2. Differentiate categories of human memory and discuss the relevant neuroanatomical systems.
3. Differentiate Broca’s and Wernicke’s aphasia.
4. Discuss dementia and relate its associated cognitive signs to associational cortex.

TUTORIAL OUTLINE

I. Temporal associational cortex

A. visual recognition
1. harbors higher order visual pathways in the ventral (“what”) processing stream,
in addition to associational cortex that integrates information from other
sensory systems to form representations of objects (see Figure 12.182)
2. damage can lead to agnosias (“not knowing”)
a. in general, agnosias refer to deficits in the recognition and/or naming of
specific objects, despite an awareness of their presence
b. e.g., prosopagnosia (“prosopo” Greek, = face or person): inability to
recognize faces
i. in the inferior temporal gyrus and the lateral occipitotemporal
gyrus (fusiform gyrus), there are neurons that respond
selectively to (primate) faces (see Figure 26.11 & 26.13)
ii. some cells are selective for only certain views of faces (see
Figure 26.13C& 26.14)

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 Associational Cortex of the Temporal Lobe

iii. damage to the right inferior temporal lobe commonly leads to

prosopagnosia
B. formation of declarative (episodic) memory
1. different categories of memory
a. declarative vs procedural (non-declarative) (see Figure 31.1)
b. immediate; working memory; long-term memory(see Figure 31.2)
2. brain systems for the acquisition and storage of memory
a. declarative memory
i. acquisition requires hippocampal formation and associated
temporal cortex (see Figure 31.9)
ii. damage to the medial temporal lobe produces amnesia
(pathological forgetting)
iii. memory storage involves widespread cortical areas that are
specialized for processing particular modes of information (e.g.,
sensory-specific areas) (see Figure 31.14)
b. procedural memory (i.e., motor learning) (see Figure 31.17)
i. acquisition of motor skills involves cerebellum and the motor
cortex
ii. storage involves widespread cortical regions, including
premotor areas and the cerebellum
c. memory and aging (see Figure 31.18 & 31.19)
i. with normal aging, the brain continues to change
- overall brain sizes decreases
- synaptic density (connections) decreases
- myelination becomes less compact (efficiency of
information processing likely decreases)
- but the numbers of neurons is not changing significantly
(neuronal loss in pathological, not part of normal healthy
aging)
ii. like most organ systems, the brain benefits from cardiovascular
fitness across the lifespan
- physical exercise is the single best activity to support brain
health into older adulthood
- there is less clear evidence suggesting that cognitive
exercise is also beneficial
- there is no compelling evidence for the benefits of dietary
supplements (assuming a balanced diet) in supporting brain
health in older adulthood (caveat emptor!)

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 Associational Cortex of the Temporal Lobe

iii. dementia and Alzheimer’s disease (see Box 31D)

- dementia is a syndrome characterized by memory deficit
with at least one other cognitive deficit
- Alzheimer’s disease is the most common cause of dementia
- one of the first and most severely affected brain systems is
the medial temporal lobe memory system
- the cortical distribution of neuritic tangles and plaques
helps to explain what aspects of cognition are afflicted with
disease progression
C. language
1. the ability to associate arbitrary symbols with specific meanings, and the ability
to use such symbols to report thoughts and emotions
2. linguistic abilities are localized to specific divisions of associational cortex in the
temporal and frontal lobes
a. cerebral centers devoted to language processing transcend the essential
sensory and motor functions associated with hearing or reading words
and speaking, signing or writing words
b. there are separate divisions of the associational cortex devoted to the
reception and expression of linguistic symbols (see Figure 27.2)
c. reception of language
i. Wernicke’s area (posterior speech cortex) (named for the
German neurologist, Carl Wernicke)
ii. frequently located in the posterior portion of the superior
temporal gyrus, but important nodes in an extended network of
lateral temporal cortex may be distributed across the lateral
aspect of the temporal lobe and into the inferior parietal lobule
iii. Wernicke’s “area” (network) integrates sensory information
that represents language
iv. damage results in fluent expression of language, but impaired
comprehension of language (Wernicke’s aphasia) (see Table
27.1)
d. expression of language
i. Broca’s area (named for the French physician, Paul Broca)
ii. located in the posterior portion of the inferior frontal gyrus
iii. coordinates the production of language (expression)
iv. “pre-motor” function for language (consistent with its position
in the posterior and inferior frontal lobe; may be considered a
functional component of the lateral premotor cortex)

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 Associational Cortex of the Temporal Lobe

v. damage results in normal comprehension of language, but

impaired expression of language (Broca’s aphasia) (see Table
27.1)
visit BrainFacts.org for a compelling and inspiring account of one family’s
coping with Broca’s aphasia; click here

e. linguistic abilities are lateralized

i. corresponding divisions of the association cortex in the two
hemispheres contribute to language processing; however, the
specific contributions of the two hemisphere are different
- for approximately 95% of us, Wernicke’s and Broca’s
areas are lateralized to the left hemisphere
- however, Brodmann’s Areas 22 (Wernicke’s) and 44/45
(Broca’s) on the right side also contribute to language
function (prosody)
- Area 22 in the right hemisphere is involved with
perceiving the emotional content of language
- Area 44/45 in the right hemisphere can produce
rudimentary words and phrases in subjects with
damage to the left frontal lobe; the right
hemisphere is also involved in producing the
modulations of vocal tone that imbue speech
with emotional content
ii. gender differences?
- lateralization of language functions appears to be less
obvious in about 20% of women
- women are less likely to develop language impairments
following middle cerebral artery stroke than men

STUDY QUESTIONS
Q1. What neurological problems would you expect with a patient who suffered a stroke involving
branches of the right posterior cerebral artery that supply inferior temporal cortex?
A. profound inability to produce fluent speech
B. diminished capacity to infuse emotional content into speech
C. profound difficulty understanding the semantic content of speech
D. diminished capacity to appreciate emotional nuance in speech
E. loss of ability to read
F. profound difficulty naming familiar faces
G. profound difficulty perceiving the movement of objects and people in the visual world
H. profound amnesia
I. profound difficulty recalling events from childhood

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 Associational Cortex of the Temporal Lobe

Q2. What neurological problems would you expect with a patient who suffered a stroke involving
inferior branches of the right middle cerebral artery that supply lateral temporal cortex?
A. profound inability to produce fluent speech
B. diminished capacity to infuse emotional content into speech
C. profound difficulty understanding the semantic content of speech
D. diminished capacity to appreciate emotional nuance in speech
E. loss of ability to read
F. profound difficulty naming familiar faces
G. profound difficulty perceiving the movement of objects and people in the visual world
H. profound amnesia
I. profound difficulty recalling events from childhood

5
 Associational Cortex of the Frontal Lobe

Medical Neuroscience | Tutorial Notes

Associational Cortex of the Frontal Lobe

MAP TO NEUROSCIENCE CORE CONCEPTS1

NCC5. Intelligence arises as the brain reasons, plans, and solves problems.
NCC7. The human brain endows us with a natural curiosity to understand how the world works.

LEARNING OBJECTIVES
After study of the assigned learning materials, the student will:
1. Discuss the major functions that are localized to the associational cortex of the frontal lobe.

TUTORIAL OUTLINE

I. Frontal associational cortex: the prefrontal cortex

A. two major cortical territories in the frontal lobe
1. posterior motor cortex (premotor cortex and primary motor cortex)
2. prefrontal cortex: cortex anterior and medial to the motor cortex (“pre”-frontal
because it is “before”—anterior to—the motor cortex)
B. two divisions of the prefrontal cortex: dorsal-lateral and ventral (orbital)-medial
1. dorsal-lateral prefrontal cortex: executive functions
a. involved in planning behavior based on integration of sensory
information together with other sources of input (e.g., memory,
interoception, emotion) that inform cognition
b. exemplified by working memory
- information must be held “on-line” for the execution of an
appropriate behavioral response (e.g., looking for a lost set of
keys or a familiar face in a crowd)
- neurons in the prefrontal cortex respond during the delay phase
of a working memory task (when information must be held “on-
line” in order to guide behavior) (see Figure 26.172)

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 Associational Cortex of the Frontal Lobe

c. dorsal-lateral prefrontal networks are among the last cortical networks

to develop, at least in terms of myelination and stability in the integrity
of functional connections
d. once mature, dorsal-lateral prefrontal networks play an important role
in making use of prior experience to guide subsequent behavior
i. this is key for moderating or suppressing inappropriate
behaviors
ii. especially important in complex, real-world situations where
the “rules” that guide social behavior are dynamic
e. damage to dorsal-lateral prefrontal networks can lead to deficits in
working memory, but also to perseveration (a continuation of prior
behavior, even after reinforcement contingencies have changed) (see
Box 26B)
i. people with dorsal-lateral prefrontal injury are impaired in
planning appropriate behavior in complex, dynamic scenarios
ii. disruption of executive functions
2. orbital-medial (ventral-medial) prefrontal cortex
a. involved in emotional processing, reason, interpretation of social cues,
planning appropriate social behavior, and formation of advantageous
decisions in real-life circumstances
b. Phineas Gage: an illustration of the disruption of social behavior
following damage to the orbital-medial prefrontal cortex: “A Wonderful
Journey Through Skull and Brains” (Vermont Mercury, October 13,
1848)

STUDY QUESTION
A patient developed a meningioma in the anterior 2-3 cm of the falx cerebri. What behavioral problems
would you expect with this patient?
A. profound inability to produce fluent speech
B. difficulty walking
C. diminished capacity to formulate advantageous, real-life decisions
D. perseveration of action
E. profound difficulty recalling recent events

2
 Sleep and Wakefulness

Medical Neuroscience | Tutorial Notes

Sleep and Wakefulness

MAP TO NEUROSCIENCE CORE CONCEPTS1

NCC2. Neurons communicate using both electrical and chemical signals.
NCC3. Genetically determined circuits are the foundation of the nervous system.
NCC8. Fundamental discoveries promote healthy living and treatment of disease.

LEARNING OBJECTIVES
After study of the assigned learning materials, the student will:
1. Discuss circadian rhythms in homeostatic functions and overt behaviors.
2. Discuss the underlying neural systems that account for circadian rhythmicity.
3. Describe the basis of “brain waves” (electroencephalographic activity).
4. Characterize the stages of non-REM and REM sleep.
5. Describe the functional states of the thalamocortical projection neurons in non-REM sleep
and waking states.

TUTORIAL OUTLINE

I. Introduction
A. human sleep patterns
1. how much is enough? (see Figure 28.1A2)
2. age matters (see Figure 28.1B)
B. sleep essentials
1. why do we sleep?
2. sleep is essential for optimal health status (see Figure 28.3)

II Circadian cycles
A. diverse physiological (homeostatic) functions and overt patterns of behavior cycle with a
period of approximately 24 hours (see Figures 28.2 and 28.4)

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 Sleep and Wakefulness

1. oxidative metabolism and core body temperature decline during (or just prior
to) the onset of sleep
2. certain hormones (e.g., cortisol, growth hormone) “spike” in relation to intervals
of nightly sleep
3. daily cycles of activity and sleep:
a. average 24.0 hours
b. if isolated from external cues, daily cycles “free-run” with a period of
just longer 24 hours
c. indicates that circadian rhythms are generated internally, but entrained
to environmental cycles of day and night
B. Suprachiasmatic nucleus (SCN) and photoentrainment
1. the SCN is located in the periventricular zone of the anterior hypothalamus, just
above the optic chiasm (see Box 21A)
2. SCN neurons maintain an intrinsic circadian rhythm (see Box 28B)
a. SCN lesions abolish circadian rhythms of sleep and wakefulness
b. isolated SCN neurons show circadian rhythms
view an online animation that accompanies Neuroscience, 5th. Ed.,
Chapter 28: Animation 28.01 A Molecular Clock [click here]
3. neural mechanism of photo-entrainment (see Figure 28.5)
a. SCN receives retinal input via the retino-hypothalamic tract from newly
discovered, photosensitive ganglion cells
b. SCN activates projection neurons in the paraventricular nucleus (medial
hypothalamus) that innervate sympathetic preganglionic neurons in the
intermediolateral cell column
c. sympathetic postganglionic neurons in the superior cervical ganglion
innervate the pineal body (gland), which synthesizes and secretes the
sleep promoting hormone, melatonin
d. melatonin modulates the activity of hypothalamic and reticular
formation centers that, in turn, regulate the sleep-wake cycle

III. Sleep stages

A. sleep comprises a series of successive stages that occur in a characteristic sequence and
cycle during a normal night’s sleep (see below)
B. first, a primer on electroencephalography (EEG) (see Box 28C)
1. electrical activity generated by the billions of neurons and their synaptic
connections within the cerebral cortex is reflected in the electrical potentials
that can be recorded from the surface of the scalp
2. the amplitude and frequency of the surface EEG (“brain waves”) is a function of:

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 Sleep and Wakefulness

a. the number of active neurons that underlie any electrode

b. the firing rate of the active neurons
c. the synchrony of the active population (see Box 28C, Figure C)
3. EEG activity is conventionally recognized in one of several frequency bands that
have characteristic amplitudes:
a. delta rhythms = 1-4 Hz, high amplitude (slow-wave sleep)
b. theta rhythms = 4-7 Hz, moderate amplitude (active exploration)
c. alpha rhythms = 8-12 Hz, moderate-to-high amplitude (quiet rest)
d. beta rhythms = 12-60 Hz, low amplitude (attentive, concentrating)
4. EEG recordings are used to diagnosis normal (e.g., sleep, wakeful conscious) and
pathological (e.g., seizure, coma, persistent vegetative) brain states (see table)
C. electroencephalographic and physiological stages of sleep (see Figure 28.6 & 28.7)
1. stage 1: primarily characterized by feelings and behaviors associated with
extreme drowsiness and EEG rhythms that are slightly slower in frequency and
greater in amplitude than those observed in most waking states
2. stage 2: next deeper stage of sleep
a. further decrease in EEG frequency and further increase in amplitude
b. this “baseline” rhythm is interrupted intermittently by brief, high-
frequency clusters of spike activity called sleep spindles
3. stage 3: moderate to deep levels of sleep, characterize by a cessation of sleep
spindles and still further decreases in EEG frequency and further increase in
amplitude
4. stage 4: also called “slow-wave sleep”; this is the deepest level sleep and it is
characterize by prominent, high amplitude delta waves
5. REM (= rapid eye movement) sleep (also called “paradoxical sleep”)
a. following stage 4 sleep, the cycles reverse through stage 2 sleep when
abrupt transitions to an episode of REM sleep ensues
b. paradoxically, EEG activity in REM sleep resembles the waking state
c. most (but not all) dreaming occurs in REM sleep (see below)
d. certain cortical regions are less active (“executive function” sectors of
the prefrontal cortex), while other cortical regions are more active
(limbic forebrain structures) (see Figure 28.10)
i. evidently, this helps explains why dreams typically are
characterized by heightened emotionality and, sometimes, by
inappropriate social content
d. during REM sleep, a number of physiological functions are modulated
(see Figure 28.7)

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 Sleep and Wakefulness

i. rapid eye movements are expressed

ii. but most large skeletal muscles (except for respiration
musculature) are actively hypotonic
iii. certain visceral motor activities (cardiac output, respiration,
blood pressure) are increased
iv. thermoregulation ceases
v. in men, penile erection occurs; in women, vaginal lubrication
occurs
e. a normal night’s sleep involves multiple cycles through deeper stages of
sleep, back “out” to REM sleep, and back into deeper stages, with
progressive increases in the duration of REM sleep through the night
f. although sleep is essential for life, REM sleep is not
g. however, the prevalence of dreams in REM sleep suggests that its
overall functions may relate to the occurrence of dreams (see below)
D. dreams : why? (no consensus)
1. Freud: “ego” relaxes its hold on the “id”
2. maintenance: rehearse less common behaviors that are not often activated in
waking states (e.g., intense emotional states, aggression)
3. unlearning: erases non-adaptive (unwanted) memories
4. learning: consolidates learning and memory (synaptic plasticity)
5. epiphenomenon: REM important, but not dreams per se

IV. Neural circuits governing sleep

A. transitions of brain state from one stage of sleep to another involve a complex interplay
of multiple neurochemical systems in the hypothalamus and the brainstem reticular
formation (see Figure 28.8, 28.11, and Table 28.1)
1. waking and REM sleep states are promoted by the activation of cholinergic and
noradrenergic systems in the brainstem
a. these systems, in turn, activate other diffusely projecting
neurotransmitter systems in the reticular formation and hypothalamus
b. when waking up, cholinergic, aminergic, serotonergic, histaminergic,
and orexinergic neurotransmitter systems activate (directly and
indirectly) widespread regions of the CNS (see Figure 28.11)
c. when transitioning from non-REM to REM sleep:
i. cholinergic input from the brainstem increases, but serotonergic
and noradrenergic input decreases

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 Sleep and Wakefulness

ii. in REM sleep, descending inhibitory (GABAergic and glycinergic)

projections inhibit alpha motor neuron activity in the ventral
horn of the spinal cord (see Figure 28.8)
2. non-REM sleep stages are induced by the suppression of these activating
systems by inhibitory neurons in the preoptic region of the hypothalamus,
which in turn are activated by the basal forebrain
a. sleep is promoted by the accumulation of extracellular adenosine in
certain basal forebrain nuclei
i. adenosine builds up in cells during active periods when energy
utilization is high and ATP is being consumed
ii. excess adenosine is released (non-synaptically) by facilitated
transport/passive diffusion and binds to specific receptors on
neurons and glia
iii. thus, extracellular adenosine is a “signal” reflecting neuronal
energy stores and recent levels of neuronal activity
iv. in the basal forebrain, adenosine levels increase when awake
and decline while sleeping
v. evidently, caffeine and theophylline are stimulants because
they antagonize adenosine receptors
b. basal forebrain nuclei activate the ventrolateral preoptic nucleus
(VLPO), which inhibit the hypothalamic histaminergic system
(tuberomammillary nucleus) and the activating systems of the
brainstem
B. thalamocortical interactions during wakefulness/REM sleep and non-REM sleep
1. thalamocortical projection neurons show bi-stable functional states: oscillatory
and tonically active (see Figure 27.12)
a. oscillatory, bursting state
i. neurons in this state display short bursts of action potentials
that ride upon prolonged calcium spikes
ii. between burst events, the membrane potential is
hyperpolarized
iii. hyperpolarized state is induced by:
- withdrawal of brainstem cholinergic and noradrenergic
stimulation
- interactions of specific relay neurons and inhibitory
neurons of the thalamic reticular nucleus (see Figure
27.13)
iv. in this state, thalamocortical neurons do not respond to
afferent input; thus transmission of sensory signals is impeded

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 Sleep and Wakefulness

and sensory cortical areas are “disconnected” from the outside

(and internal) world
v. typically, this firing state dominates in non-REM sleep
b. tonically active, firing state
i. neurons in this state are relatively depolarized and capable of
entering tonic modes of firing
ii. depolarized state is induced by the activation of cholinergic and
noradrenergic systems
iii. in this state, sensory signals are transmitted to sensory cortex
and perception (generated by sensory experience or by the
partial reactivation of stored experience) is possible
iv. typically, this firing state dominates in both waking states and
REM sleep
V. Sleep disorders
A. insomnia
1. impairment associated with the inability to fall asleep, stay asleep, or
experience restoration from sleep given adequate opportunity to sleep
2. affects about 15% of the population
B. circadian rhythm disorders
1. misalignment between a person’s sleep pattern and the desired or societal
norm sleep pattern
C. sleep apnea
1. mechanical obstruction is the most common and clinically important cause
2. predisposing factors: obesity, retrognathia, large tonsils, deviated septum
D. narcolepsy (“sleep attacks”)
1. inappropriate intrusion into waking state of fragments of REM sleep
a. cataplexy: partial or complete paralysis induced by strong emotion
b. residual paralysis while awake around sleep/wake transition
c. hallucinations around sleep/wake transition
2. attributable to a defect in hypocretin/orexin type-2 receptor gene and/or
abnormally low hypocretin/orexin activity
E. restless leg syndrome
1. unpleasant sensations in the legs that produce an urge to move them to obtain
relief
2. associated with insufficient Fe in substantia nigra, pars reticulata, suggesting
possibility of dopamine dysfunction in putamen

6
 Overview of the Limbic Forebrain

Medical Neuroscience | Tutorial Notes

Overview of the Limbic Forebrain

MAP TO NEUROSCIENCE CORE CONCEPTS1

NCC1. The brain is the body's most complex organ.

LEARNING OBJECTIVES
After study of the assigned learning materials, the student will:
1. Discuss the localization of the amygdala and the hippocampus in the medial temporal lobe.
2. Discuss the major functions associated with the limbic forebrain.

NARRATIVE
by Leonard E. WHITE and Nell B. CANT
Duke Institute for Brain Sciences
Department of Neurobiology
Duke University School of Medicine

Overview
Now that we have nearly completed our brief survey of human brain anatomy, let’s make one final pass
through the forebrain, focusing on structures that have been considered parts of the “limbic system”. A
subset of these are crucial for understanding the brain basis of human emotion, cognition, and biological
psychiatry, so this survey would not be complete without another look at the human brain with these
components in view.
In the accompanying video, our focus will be on localizing the amygdala and the hippocampus in the
medial temporal lobe. Here in this tutorial text, we will provide a brief overview of the limbic forebrain
and discuss some of the known major functions associated with the major collections of cortical and
subcortical structures associated with this complex ventral-medial rim (“limbus”) of forebrain.
Anatomy of the limbic forebrain
Attempts to understand the control of emotional behavior have a long history. In 1937, James Papez
first proposed that specific brain circuits are devoted to emotional experience and expression. In seeking
to understand what parts of the brain serve this function, he began to explore the medial aspects of the
cerebral hemisphere. In 1878, Paul Broca used the term “limbic lobe” (le grand lobe limbique) to refer to
the part of the cerebral cortex that forms a rim (“limbus” is Latin for rim) around the corpus callosum
and diencephalon on the medial face of the hemispheres. Two prominent components of this region are
the cingulate gyrus, which lies above the corpus callosum, and the parahippocampal gyrus, which lies in

1
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 Overview of the Limbic Forebrain

the medial temporal lobe. For many years, these two structures, along with the olfactory bulbs, were
thought to be concerned primarily with the sense of smell. Indeed, Broca considered the olfactory bulbs
to be the principal source of input to the limbic lobe. Papez, however, speculated that the function of
the limbic lobe might be more related to emotions. He knew that the hypothalamus influences the
expression of emotion; he also of course knew that emotions reach consciousness and that higher
cognitive functions affect emotional behavior. Ultimately, Papez showed that the cingulate cortex and
hypothalamus are interconnected via projections from the mammillary bodies (part of the posterior
hypothalamus) to the anterior nucleus of the thalamus, which projects in turn to the cingulate gyrus; the
cingulate gyrus (like many other cortical regions) projects to the hippocampus. Finally, he showed that
the hippocampus (actually, the subiculum, a division of the hippocampal formation) projects via the
fornix (a large fiber bundle) back to the hypothalamus and septal region. Papez suggested that these
pathways, which became known as the “Papez circuit,” provide the connections necessary for cortical
control of emotional expression.

Figure 1. Medial view of the human brain sectioned along the midsagittal plane. In this view, several
components of the limbic forebrain are visible, but other important components are not. Refer to the terms in
bold typeface in the main text and see if you can locate them in this image. You should also note the location
(by reference to the accompanying video) of those structures highlighted in bold that are not visible in this
image. You should review tutorials in Unit 1 as needed if you are not confident in your ability to localize these
anatomical structures that are associated with the limbic forebrain.

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 Overview of the Limbic Forebrain

Over time, the concept of a forebrain circuit for the control of emotional expression has been revised to
include parts of the orbital and medial prefrontal cortex; ventral portions of the basal ganglia—most
importantly, the nucleus accumbens; the mediodorsal nucleus of the thalamus (a different thalamic
nucleus than the one Papez emphasized); and the amygdala, a large nuclear mass in the temporal lobe
anterior to the hippocampus. This set of structures, together with the parahippocampal gyrus and
cingulate cortex, is generally referred to as the “limbic system” (see Figure 1). However, this so-called
system (so-called primarily for historical reasons) is not unimodal, as the term ‘system’ implies. Rather,
the limbic ‘system’ is involved in the regulation of visceral motor activity, emotional experience and
expression, olfaction, and memory, to name some of its better understood functions. Furthermore,
some of the structures that Papez originally described (the hippocampus, for example) now appear to
have little primary role in emotional processing, whereas the amygdala, which Papez hardly mentioned,
clearly plays a major role in the experience and expression of emotion2.
In order to know which groups of structures in the limbic forebrain are associated mainly with particular
aspects of sensation and cognition, it is helpful to recognize three basic groupings or divisions:
 an olfactory division, concerned with the encoding of olfactory signals and engaging behaviors
motivated by air-borne stimuli;
 a parahippocampal division, centered in the medial temporal lobe, that is mainly concerned
with explicit representation and the acquisition and retrieval of declarative (episodic) memory;
 an amygdala/orbital prefrontal division encompasses a network of telencephalic and
diencephalic structures with the amygdala and related sectors of the orbital and medial
prefrontal cortex as key nodes; this division is primarily concerned with implicit representation,
which becomes manifest in the experience and expression of emotion and emotional behavior.
Thus, it is the amygdaloid/orbital prefrontal division that is most germane for understanding the brain
basis of emotion and motivated behavior. Through an illuminating history of empirical findings and
clinical observations in both experimental animals and humans, it is now clear that the amygdala
mediates neural processes that invest sensory experience with emotional significance in a form of
associative learning, particularly when the sensory
experience signals threat. Indeed, it is not too much of a
stretch to characterize the amygdala (and its telencephalic
and diencephalic connections) as an “early warning system”
being especially well-tuned to social cues and
environmental stimuli that signal threat.

Figure 2. The human amygdala in histological section. View of

the temporal lobe in a coronal section that was stained with
silver salts to reveal the presence of myelinated fiber bundles,
which subdivide major nuclei and cortical regions. Three major
groups of subdivisions can be recognized: a basal-lateral group,
a medial group, and a central group. (image courtesy of J.L.
Price and L.E. White)

2
Many authors now advocate dismissal of the term “limbic system” as an outmoded and misleading concept, and rather
emphasize the diverse functions associated with the various components of an expansive constellation of structures in the
ventral-medial forebrain.

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 Overview of the Limbic Forebrain

Neuroanatomically, the amygdala is a complex mass of gray matter buried in the anterior-medial portion
of the temporal lobe, just rostral to the hippocampus (Figure 2). It comprises multiple, distinct subnuclei
and cortical regions that are richly connected to nearby cortical areas on the ventral and medial aspect
of the hemispheric surface. The amygdala (or amygdaloid complex) can understood in terms of three
major functional and anatomical subdivisions, each of which has a unique set of connections with other
parts of the brain. The medial group of subnuclei has extensive connections with the olfactory bulb and
the olfactory cortex. The basal-lateral group, which is especially large in humans, has major connections
with the cerebral cortex, especially the orbital and medial prefrontal cortex and the associational cortex
of the anterior temporal lobe (Figure 3). These cortical territories associate information from every
sensory modality (including information about visceral activities) and can thus integrate a variety of
inputs pertinent to moment-to-moment experiences. In addition, the basal-lateral group projects to the
thalamus (specifically, to the mediodorsal nucleus), which projects in turn to these same cortical areas.
This same group also innervates neurons in the nucleus accumbens that receive the major cortico-
striatal projections from the prefrontal cortex and parahippocampal gyrus. Lastly, the central group of
nuclei is characterized by connections with the hypothalamus and brainstem, linking the amygdala with
autonomic, neuroendocrine and somatic effector systems.

Figure 3. The amygdala (specifically,

the basal-lateral group of nuclei)
participates in a “triangular” circuit
linking the amygdala, the thalamic
mediodorsal nucleus (directly and
indirectly via the ventral parts of the
basal ganglia), and the orbital and
medial prefrontal cortex. These
complex interconnections allow
direct interactions between the
amygdala and prefrontal cortex, as
well as indirect modulation via the
circuitry of the ventral basal ganglia.

Considering all these seemingly arcane anatomical connections, the amygdala emerges as a key node in
a network that links together the cortical and subcortical brain regions involved in emotional processing
and the expression of emotional behavior. More generally, the amygdala and its connections to the
prefrontal cortex and basal ganglia are likely to influence the selection and initiation of behaviors aimed
at obtaining rewards and avoiding punishments (recall that the process of program selection and
initiation is an important function of basal ganglia circuitry). The parts of the prefrontal cortex
interconnected with the amygdala are also involved in organizing and planning future behaviors. Thus,
the amygdala may provide emotional input to overt (and covert) deliberations of that bias decision-
making in prefrontal networks.
Finally, it is likely that interactions between the amygdala, the neocortex and related subcortical circuits
account for what is perhaps the most enigmatic aspect of emotional experience: the highly subjective
“feelings” that attend most emotional states. Although the neurobiology of such experience is not
understood, it is reasonable to assume that emotional feelings arise as a consequence of a more general
cognitive capacity for self-awareness. In this conception, feelings entail both the immediate conscious
experience of implicit emotional processing (arising from amygdala–neocortical circuitry) and the
explicit processing of semantically based thought (arising from hippocampal–neocortical circuitry). It is

4
 Overview of the Limbic Forebrain

plausible to conceptualize feelings as the product of an ‘emotional working memory’ that sustains
neural activity related to the processing of these various elements of emotional experience. Given the
evidence for working memory functions in the prefrontal cortex, this portion of the frontal lobe—
especially the orbital and medial sector—is the likely neural substrate where such associations are
maintained in conscious awareness.

STUDY QUESTION
Which of the following statements best differentiates the hippocampus from the amygdala?
A. The hippocampus is anterior to the amygdala in the medial temporal lobe.
B. The amygdala is involved in implicit representation, and the hippocampus is involved in explicit
representation.
C. The amygdala is a cortical structure, and the hippocampus is a subcortical structure.
D. The hippocampus forms the floor of the temporal horn of the lateral ventricle, and the
amygdala forms the medial wall of the third ventricle.
E. The amygdala communicates with the hypothalamus via the fornix, and the hippocampus
communicates with the hypothalamus via the anterior commissure.

5
 Neurobiology of Emotion

Medical Neuroscience | Tutorial Notes

Neurobiology of Emotion

MAP TO NEUROSCIENCE CORE CONCEPTS1

NCC1. The brain is the body's most complex organ.
NCC5. Intelligence arises as the brain reasons, plans, and solves problems.
NCC7. The human brain endows us with a natural curiosity to understand how the world works.

LEARNING OBJECTIVES
After study of the assigned learning materials, the student will:
1. Characterize emotion as associative learning.
2. Differentiate the role of the amygdala and the orbital-medial prefrontal cortex in emotion.
3. Discuss involvement of limbic forebrain circuitry in decision-making.

TUTORIAL OUTLINE

I. Emotion and body state

A. William James’s view of emotion (ca. 1900)
1. Emotion is the product of changes in body state
a. emotion-provoking stimuli activate somatic and visceral sensory
receptors
b. peripheral autonomic and skeleto-muscular activities are engaged
c. peripheral responses are detected
d. emotion elicited by peripheral feedback
2. thus, as James put it, “we are afraid because we tremble”
B. modern theories affirm the importance of changes in body state, but question whether
the “body-loop” is obligatory for emotional experience

II. Emotion as associative learning

A. emotions are produced by the association of sensory stimuli (secondary reinforcers)
with primary reinforcers (rewards and punishers) (see Figure 29.62)

1
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 Neurobiology of Emotion

1. rewards: anything for which we will work (e.g., pleasant taste or tactile
sensation)
2. punisher: anything that an animal we will avoid (e.g., aversive taste or pain)
B. emotions are the states of body and brain signaling the anticipation of reward or
punishment

STUDY QUESTION
What change in excitatory synapses is a major factor in sustaining long-term potentiation?
A. the insertion of additional voltage-gated calcium channels in presynaptic terminals
B. the insertion of additional GABA-A receptors in postsynaptic membranes
C. the removal of excess NMDA glutamate receptors from postsynaptic membranes
D. the removal of excess D1 dopamine receptors from postsynaptic membranes
E. the insertion of additional AMPA receptors in postsynaptic membranes

III. Brain systems for emotional processing (where emotional learning takes place)
A. two main structures in the ventral and medial forebrain—the so-called “limbic”
forebrain—are critically involved in emotional processing: the amygdala and the
orbital-medial prefrontal cortex (see Figure 29.4)
B. output to “downstream” effector systems involves both classical motor pathways
(pyramidal system) and less-well defined (extrapyramidal) pathways that mediate
emotional expression (recall the parallel pathways that govern emotional and volitional
facial expressions) (see Figure 29.2)
C. amygdala (see Box 29B; Figure 29.9)
1. associates sensory stimuli with rewards and punishers
2. especially important in threat/fear processing and fear-based social
assessments
3. deficits produced by amygdala lesions can be understood in terms of a failure of
emotional associative learning and an absence of threat/fear signaling
D. orbital-medial prefrontal cortex
1. involved in emotional processing, interpretation of social cues, planning
appropriate social behavior, and formation of advantageous decisions in real-life
circumstances (≈ reason)
2. emotional learning, especially when primary reinforcers are scents and food
3. involved in ongoing analysis and modification of behavior when reinforcement
contingencies are rapidly changing (emotional re-learning)
4. necessary for the assessment of future consequences and the implementation
of advantageous decisions (see below)

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 Neurobiology of Emotion

IV. Emotion and reason

A. when the orbital-medial prefrontal cortex is damaged ...
1. no impairments in sensorimotor control
2. no impairments on standard neuropsychological assessment; but
3. impaired emotional experience and expression
B. impaired rational decision making, especially in personal and social affairs (exemplified
by the famous case of Phineas Gage)
C. pathological inability to make advantageous decisions in real life situations
D. suggests that emotional processing is essential for rational decision making
E. somatic marker hypothesis (A. Damasio, 1994)
1. rational decision making entails covert (subconscious) evaluation of future
consequences
2. mental images representing possible outcomes trigger somatic states that
‘mark’ the mental images with emotional valence
3. somatic states may be truly somatic (involve activity of visceral and somatic
motor effector systems) or vicarious (involve only neural representations of
sensory activity at the level of the somatic sensory cortex)
4. thus, somatic markers bias deliberations toward implementation of
advantageous decisions and away from disadvantageous decisions

3
 Neurobiology of Addiction

Medical Neuroscience | Tutorial Notes

Neurobiology of Addiction

MAP TO NEUROSCIENCE CORE CONCEPTS1

NCC1. The brain is the body's most complex organ.
NCC3. Genetically determined circuits are the foundation of the nervous system.
NCC4. Life experiences change the nervous system.

LEARNING OBJECTIVES
After study of the assigned learning materials, the student will:
1. Discuss the brain’s reward system.
2. Discuss involvement of limbic forebrain circuitry in mediating addictive behavior.

TUTORIAL OUTLINE

I. Brief review of basal ganglia structure and function

A. basal ganglia
1. collection of nuclei located deep in the anterior telencephalon that are
intimately related to the functions of the cerebral cortex
a. receive widespread inputs from the cerebral cortex
b. after several steps of processing, basal ganglia output is directed to the
thalamus, which in turn projects back to the cerebral cortex
c. thus, the overall function of the basal ganglia is to modulate thalamo-
cortical activity
2. there are multiple parallel processing “streams” through the basal ganglia (see
Box 18D2); three important streams are:
a. dorsal motor stream (motor loop)
b. dorsal cognitive (“executive”) stream (prefrontal loop)
c. ventral limbic (“emotional”) stream (limbic loop)
B. general sense of basal ganglia function:
1. processes executive commands for the initiation of appropriate behavior and
the suppression of inappropriate behavior

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 Neurobiology of Addiction

2. for the ventral limbic stream, activation of the direct pathway facilitates the
processing and/or prediction of reward

II. Addiction
A. mediated by “reward” circuitry of the ventral limbic stream in the basal ganglia, which
receives input from the amygdala, hippocampus and orbital-medial prefrontal cortex
(see Figure 29.10)
1. output is directed toward orbital-medial prefrontal cortex (among other limbic
regions) where valence (rewards and punishers) and emotion are integrated
2. dopamine amplifies the output of the ventral limbic stream by facilitating
activation of the direct pathway and suppressing activation of the indirect
pathway
3. dopamine signals the presence and/or prediction of rewarding conditions (see
Figure 29.12)
B. addiction leads to an increase in reward-associated release of dopamine in the ventral
striatum (nucleus accumbens) (see Figure 29.11)
C. but addiction also may lead to a decrease in the release of dopamine in response to
non-addictive (normal) rewarding experiences
D. because of “B” & “C” above, addicts become increasingly oriented toward obtaining the
rewarding experience that has become the object of the addiction

STUDY QUESTION
Based on current evidence from studies of animal models of addiction, what do you expect to happen in
the brain of a person who is addicted to cocaine when this person enters a room that happens to have
drug paraphernalia on a table in plain site?
A. There is likely a burst of action potentials generated in ventral tegmental area neurons when the
objects on the table are recognized as pertaining to cocaine consumption.
B. There is likely a suppression of action potentials in ventral tegmental area neurons when the
objects on the table are recognized as pertaining to cocaine consumption.
C. There is likely a burst of action potentials generated in nucleus accumbens neurons that
contribute to the indirect pathway when the objects on the table are recognized as pertaining to
cocaine consumption.
D. There is likely a burst of action potentials generated in ventral pallidum neurons when the
objects on the table are recognized as pertaining to cocaine consumption.
E. There is likely a suppression of action potentials in mediodorsal thalamic neurons when the
objects on the table are recognized as pertaining to cocaine consumption.